molecules Review Synthetic and Naturally Occurring Heterocyclic Anticancer Compounds with Multiple Biological Targets Richard Kwamla Amewu 1 , Patrick Opare Sakyi 1,2, Dorcas Osei-Safo 1 and Ivan Addae-Mensah 1,* 1 Department of Chemistry, School of Physical and Mathematical Sciences, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 56, Ghana; ramewu@ug.edu.gh (R.K.A.); opsakyi@st.ug.edu.gh (P.O.S.); dosei-safo@ug.edu.gh (D.O.-S.) 2 Department of Chemical Sciences, School of Sciences, University of Energy and Natural Resources, Sunyani P.O. Box 214, Ghana * Correspondence: iaddae-mensah@ug.edu.gh; Tel.: +233-277-55-44-00 Abstract: Cancer is a complex group of diseases initiated by abnormal cell division with the po- tential of spreading to other parts of the body. The advancement in the discoveries of omics and bio- and cheminformatics has led to the identification of drugs inhibiting putative targets includ- ing vascular endothelial growth factor (VEGF) family receptors, fibroblast growth factors (FGF), platelet derived growth factors (PDGF), epidermal growth factor (EGF), thymidine phosphorylase (TP), and neuropeptide Y4 (NY4), amongst others. Drug resistance, systemic toxicity, and drug ineffectiveness for various cancer chemo-treatments are widespread. Due to this, efficient therapeutic agents targeting two or more of the putative targets in different cancer cells are proposed as cutting edge treatments. Heterocyclic compounds, both synthetic and natural products, have, however, contributed immensely to chemotherapeutics for treatments of various diseases, but little is known   about such compounds and their multimodal anticancer properties. A compendium of heterocyclic Citation: Amewu, R.K.; Sakyi, P.O.; synthetic and natural product multitarget anticancer compounds, their IC50, and biological targets of Osei-Safo, D.; Addae-Mensah, I. inhibition are therefore presented in this review. Synthetic and Naturally Occurring Heterocyclic Anticancer Compounds Keywords: homeostasis; metastasis; angiogenesis; apoptosis; vascularization; heterocyclic compounds; with Multiple Biological Targets. multiple biological targets Molecules 2021, 26, 7134. https:// doi.org/10.3390/molecules26237134 Academic Editor: Brullo Chiara 1. Introduction Cancer is a complex group of diseases the onset of which is characterized by abnormal Received: 25 October 2021 cell division with the potential of spreading to other parts of the body over time [1,2]. The Accepted: 22 November 2021 Published: 25 November 2021 abnormal cell differentiation is normally accompanied by drastic weight loss, prolonged cough, and abnormal lump growth [3]. The prevalence of cancer is spiraling globally. Publisher’s Note: MDPI stays neutral Currently, cancer ranks second as the leading cause of death worldwide and in the year with regard to jurisdictional claims in 2020 alone, an estimated 19.3 million new cases with 10 million deaths were recorded [4]. published maps and institutional affil- These statistics translate into an annual death rate that is a little over 50% of the annual iations. new cases. Cancers of the stomach, lung, breast, prostate/cervix, and colorectum have all been reported but the most frequently diagnosed are lung and breast cancers followed by prostate which occurs predominantly among the aging male population [5]. Sex and age have become of paramount importance in cancer susceptibility and treatment, and men are said to be more prone to infections than women [6,7]. Copyright: © 2021 by the authors. Prior to cancer becoming metastatic, its spread is initiated by pro-angiogenic factors Licensee MDPI, Basel, Switzerland. This article is an open access article consisting of vascular endothelial growth factor (VEGF) receptors, fibroblast growth factor distributed under the terms and (FGF), platelet derived growth factors (PDGF), epidermal growth factor (EGF), thymidine conditions of the Creative Commons phosphorylase (TP), neuropeptide Y4 (NY4), and platelet factor 4 (PF4), etc. [8,9]. Upon Attribution (CC BY) license (https:// initiation, the survival of these cancer cells and their proliferation are dependent on the creativecommons.org/licenses/by/ supply of oxygen, nutrients, and clearance of waste products [10,11]. All these processes 4.0/). are dependent on the sprouting of vascular networks. New blood vessels form through Molecules 2021, 26, 7134. https://doi.org/10.3390/molecules26237134 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 7134 2 of 48 a process called angiogenesis [12]. In the absence of the vascular extension, cancer cells become necrotic or undergo a process called apoptosis, limiting the proliferation rate [10]. The level of expression of necrotic or apoptotic factors is a reflection of the aggressiveness of a tumor [13,14]. Generally vascular development starts by basement membrane destruction which leads to the release of angiogenic factors. This activates endothelial cells to migrate which then proliferate and stabilize until a safeguard sets in [10,15,16]. Regulation of neoplastic vascularization as an important step in limiting cancer proliferation has received immense attention and extensive research [8,12]. To starve these tumor cells, cautious targeting of vessel sprouting activators with a foreknowledge of how they control this chemical signal is crucial in maintaining homeostasis [17,18]. Numerous cancer targets including VEGF, FGF, PGF, EGF, PDGF, topoisomerase I and II, histone deacetylase, tyrosine kinase, and transforming growth factor-alpha (TGF-α, ) have been elucidated with multiple studies focused mainly on targeting the initiator VEGF [1,19–21]. However, halting VEGF signaling has not been very effective as reports of disease progression after treatment have become rampant [22]. A number of heterocyclic anticancer agents both synthetic and naturally occurring are in use and more are still being sought after [23–26]. Some examples are as shown in Figure 1. Heterocyclic compounds (ring compounds containing C and any of the atoms N, O, and S) have been explored for their medicinal properties for the treatment of various diseases including cancer. Introduction of these heteroatoms improves solubility, polarity, and hydrogen bonding abilities leading to ADMET (Adsorption, Distribution, Metabolism, Excretion, and Toxicity) optimization of druggable candidates. Therapeutic heterocyclic agents such as 5- fluorouracil 1, orlistat 2, vandetanib 3, rapamycin 4, axitinib Molecules 20521,, s26o, xr aFOfeR nPEibER6 R,EVeIpEW ig allocatechin 7, doxorubicin 8, daunorubicin 9, and Taxol 10 (F3i gofu 50r e 1) have demonstrated high inhibition against different types of cancer cells [27–29]. FigFuigruere1 1.. CChhememicailc satrlucstturruesc touf sroemseo hfetseoromcyeclihc ecotemrpoocuyncdlsi cuscedo mforp toreuatnindgs vaursioeuds tfyopres torfe caatnicnegr. various types of cancer. Scheme 1. Synthetic routes of Brevilin A analogues [26]. Molecules 2021, 26, x FOR PEER REVIEW 3 of 50 Molecules 2021, 26, 7134 3 of 48 Brevilin A, 11, a heterocyclic sesquiterpene lactone natural product isolated from Centipeda minima exhibits anticancer properties [30]. Studies have shown that Brevilin A attenuates the signal transducer and activator of transcription (STATS 3) and Janus kinase and tyrosine kinase activity thereby inhibiting cell growth, inducing apoptosis and reducing cell metastasis [31]. Lee, Chan et al., synthesized analogues of Brevilin A and found that 13 and 14 exerted greater anticancer properties than 11. Aldol reaction of 11 and paraformaldehyde in the presence of sodium carbonate produced 12. Acetylation of 12 with p-nitrobenzoyl chloride and methacrylic anhydride afforded 13 and 14, resp ectively Figure 1. Chemica(lS scthruecmtuere1s) o[2f 6so].me heterocyclic compounds used for treating various types of cancer. ScShcehmeme e1 .1S. ySnytnhtehteitcicr oruotuetseso foBf rBerveivliinlinA Aa naanlaolgougeuse[s2 [62]6. ]. Challenges associated with cancer treatments such as drug resistance, systemic toxicity of administered drugs, and drug ineffectiveness are widespread [32,33]. Furthermore, confounding factors such as the multiple signaling nature of pathways and the propensity of most cancer cells to mutate have hindered the search for an effective therapeutic agent for combating cancers, calling for urgent search to identify new anticancer agents as drug leads [19,34]. To overcome these challenges, multi-target heterocyclic inhibitors are proposed as an option in achieving success in the fight against various forms of cancers. Emerging heterocyclic compounds with demonstrable anticancer activities include sunitinib 15, midostaurin 16, and vorinostat 17 (Figure 2). They possess multi-regulatory activity against growth factors like vascular endothelium growth factor receptor (VEGFR), platelet-derived growth factor receptor alpha (PDGFRA’s c-Kit) and tyrosine kinase 3 (FLT-3) [35]. In the same vein, gefitinib 18, erlotinib 19, lapatinib 20, and sotagliflozin 21 (Figure 2) with magnificent inhibitory potentials against human epidermal growth factor receptor 1 (HER1) and 2 (HER2) are also in phase 3 clinical trials confirming that multi-targeted therapy has a future [36,37]. This review therefore seeks to highlight the various types of heterocyclic multimodal- ity anticancer agents (synthetic and natural products) and their biological targets with some emphasis on their mechanism of action. Various systematic rigorous methodological approaches were used to search literature to identify, collate, and critically appraise a body of previously published works relevant to the topic. The search comprised of putting rele- vant key words into Scifinder, Scopus, Google scholar, PubMed, and others and appraising them for their suitability. Original hard copy offprints of published papers in our various personal archives were also consulted for relevant information [38,39]. MMoolleeccuulleess 22002211,, 2266,, 7x1 F3O4 R PEER REVIEW 44 ooff 4580 FFiigguurree 22.. Chheemiiccaall ssttrruuccttuurreess ooff ssoomee hheetteerrooccyycclliicc muullttii--ttaarrggeett aannttiiccaanncceerr aaggeennttss.. Coomppoouunnddss 1155––1177 aarree iinn cclliinniiccaall uussee wwhhiillee 1188––2211 aarree iinn vvaarriioouuss ssttaaggeess ooff cclliinniiccaall ttrriiaallss.. 2. HeTtheriso cryevcliiecwC tohmerpeofourned sseeks to highlight the various types of heterocyclic multimo- dalityH aentetircoacnyccelri caogregnatsn i(csycnotmheptoicu anndds naraetudreasl ipgrnoadteudctas)s ainntde gthraeilrc boimolpoogniceanl ttsarognetas wwiidthe saormraey eomf spthruacstius roens twheitihr mboetchhapnhiasrmm oafc oaclotigoinca. lVaanridoubiso slyosgtiecmalaitmicp roigrtoarnocues. mTheethyocdoonlsotgitiuctael aaplparrgoeacchoehso wrteorfe sutrsuecdt utore ssewaricthh ilmitemraetnusree imto piodretnatnifcye, icnotlhlaeteli, feansdci ecnricteicsa. lTlyh eaiprpdriaviesers ae bchoadrya cotfe prirsetvicisouinscllyu pduebthlieshdeidsp wlaoyrkofs arewleivdaenvta troi ethtye otof pinicte. rTmhoe lseecaurlcahr icnotmerparcitsioends o, fd pifufettrienngt rreinlegvsainzte sk,etyh ewiroprdlasn ianrtioty Sicfiafirnodmear,t iScc, oapnudsf,u Gnoctoiognlea lscghrooulapr,v PeursbaMtileidty,. aAnmd oonthgetrhse atnwde anpty- pamraiinsionga ctihdesm, p froorl itnhee,irh siustiitdaibnilei,tya.n Odrtirgyinpatol phharadn ccoopnyta oinffphreitnetrso ocfy pcluicblriisnhgesd. pFuaprtehres rimn ooruer, vthaeriboaussi cpuernsiotsntahl aatrccohnivtaeisn winesrter ualcstoio cnosnfsourldteedv efolorp rmeleenvat,ngtr ionwfotrhm, aantidonre [p3r8o,d39u]c. tion are all made of a heterocyclic nucleus. 2. HeMtearoncyynclaitcu Craolmpprooduuncdtss such as alkaloids, flavonoids, terpenoids, coumarins, antho- cyaniHnes,teisrotchyicalzico loersg, eatnci.c, ccoonmtapinouhnedtesr oacrey cdliecsriginngast,epdo asse isnstaegbrraola cdosmppecotnruenmtso of na cati vwitiidees argraiyn sotf nsturmucetruorues wdiisteha bsoe-tcha puhsianrgmoarcgoalongisicmals .anInd abdiodliotgioicna, lr iemcepnotrstatrnuccet.u Trhael ya scsoensstmiteuntet ao flahregte rcoochyocrlitc omf sotireuticetsuraems ownigths yimntmhetnicsec oimporutanndcseb iyn Mthaer sliofen shcaisenrceevse.a Tlehdeitrh dativtehresier cinhcaorarpctoerraistitoicns pinlacylusdaev tehrey dsisgpnliafiyc aonf tar owliedien vdarruiegt-yli koef ninestesramnodletacrugleatr binintedriancgtiboynsl,i mdiiftfienrg- etonxt icrimnge tsaibzeosli,t ethperior dpulactniaorni,tyin icfr eaarsoimngatwica, taenrdso flunbciltiitoyn, aln dgrlouwpe rvinergsactoinliftoyr. mAamtionga ltehne- twroepnyty[4 a0m]. iHnoet earcoidcys,c lpicroclhineme, ohtiysptiedsinliek,e aqnudi ntorylipnteo,pqhuaina czonlitnaein, q hueinteorxoaclyinclei,c pryinrigms.i dFiunre-, tphyerramzolrien, et,h1e, 2b,4a-stirci auznoiltes, tihmaitd caoznotlaei,nb einsztirmucidtiaoznos lefo, ris doexvaezloolpinme,einsto, qgurionwotlhin, ea,npdy raezporloe-, danudctiiosonx aarzeo allel (mFiagduer eof3 a) hcaenterboecfyoculinc dnuinclceoums. pounds used in the treatment of debilitat- ing dMisaenasye nsalitkueraml palraordiau,cttus bseurcchu aloss aislk, caalonicdesr,, fnlaevuoron-odidegs,e tneerrpaetnivoeiddsi,s ceoausems,afruinsg, aaln, tahnod- cbyaacnteinrisa,l iisnoftehcitaizoonlses[4, 1e–tc4.3, ]c.oTnhtaeinfo hlleotwerioncgyacrliec hreintegrso, cpyocsliscescso ma pbroouandd ssptehcattr,uimf p oref saecnttivais- tmieosi etaigesaiinnsst ynntuhmetiecroour sn atduirsaelalyseo-ccacuursriinngg coormgapnoiusnmdss., mIna yacdondfietiroann, ti-rceacnecnetr psrtroupcetrutireasl. Molecules 2021, 26, x FOR PEER REVIEW 5 of 50 assessment of heterocyclic moieties among synthetic compounds by Marson has revealed that their incorporation plays a very significant role in drug-likeness and target binding by limiting toxic metabolite production, increasing water solubility, and lowering confor- mational entropy [40]. Heterocyclic chemotypes like quinoline, quinazoline, quinoxaline, pyrimidine, pyrazoline, 1,2,4-triazole, imidazole, benzimidazole, isoxazoline, isoquino- line, pyrazole, and isoxazole (Figure 3) can be found in compounds used in the treatment of debilitating diseases like malaria, tuberculosis, cancer, neuro-degenerative diseases, Molecules 2021, 26, 7134 fungal, and bacterial infections [41–43]. The following are heterocyclic compounds th5aotf,4 i8f present as moieties in synthetic or naturally occurring compounds, may confer anti-cancer properties. Fiigurree 33.. Exxaamplleess off heetteerroccycclliicc ccheemottypeess.. 22..11.. NN--BBaasseedd MMuullttii--TTaarrggeett AAnnttiiccaanncceerr HHeetteerrooccyycclleess NN--bbaasseedd hheetteerrooccyycclliicc ccoommppoouunnddss hhaavvee aattttrraacctteedd mmuucchh iinntteerreesstt aanndd aatttteennttiioonn ffrroomm mmeeddiicciinnaall cchheemmiissttss aanndd bbioiolologgisitsst.s .ThTehier ibrrboraoda rdanragneg oef obfiobloiogliocgailc aacltiavcittiiveist iaensda wndidwe iadpe- paplipcalitcioantiso nins tihne tdheesidgens iogfn doruf gdsr uwgitshw exitchepexticoenpatli osenlaelctsievlietcyt ifvoirt yDNfoAr DviNa Ahyvdiraogheynd rboognedn- ibnogn idnitnegraicnttioerna hctaiso ncohnatrsibcountetdri btou ttehdeirto htighhei pr rhoipgehnpsirtoyp feonr sciotynffeorrricnogn afenrtrii-ncagnacnert ip-craonpceerr- ptireosp oenr tvieasrioonusv asyrinotuhsetsiycn atnhdet nicaatunrdaln caotumraplocuonmdps oinu nwdhsicinh wthheiyc hoctchuery [o4c4c]u. r [44]. 22..11..11.. SSyynntthheettiicc,, SSeemii--SSyynntthheettiicc aanndd Hyybbrriidd N--Heetteerrooccyycclleess N--bbaasseedd hheetteerrooccyycclleess ssuucchh aass2 222, ,2 32,3a, nadnd2 42(4F (igFuigruer4e) 4p)o pssoessssemss umltiu-tltair-gtaertgceatn ccaenrcienr- ihnibhiitboirtoyrayc taicvtiitvyi.tTyh. Teyhecya ucsaeuasne taangtoangiosmnisamt 9 a.4t 9µ.M4 μ(cMo m(cpoomupnodu2n2d), 222.5),0 2µ.5M0 μ(cMom (cpoomunpdou2n3d), 2an3)d, a9n.3d0 9µ.3M0 μ(cMom (cpoomupnodu2n4d) a2g4a) iangsatitnospt otoispoomiseormaseera1s.eT 1h.e Tchoem copmoupnodusnadlss oalasnot angtoangiozneikzie- kniansaessep sipndinledlper potreoitnei(nK (SKPS) Pa)t a2t8 .2588.,58.,9 81.,9a1n, dan1d9 .1497.4µ7M μ,Mre,s rpeescptievcetilyve[l4y5 ][.45P]a. tPhawthaywanya alynsails- yhsaiss shuagsg seusgtegdesthedat tthhaet tahnet iacnanticearncperro preorptierstioefst ohfe tchoem copmoupnodusndarse adreu deutoe tGo1 Ga1p aoppotpostois- sainsd ancedl lceclylc clyecalerr aersrteast taht ethGe2 G/2M/Mp hpahsaes.eI. tIth haassf ufurtrhtheerrb beeenno obbsseerrvveedd tthhaatt tthe selectivity and sttrong bbiinnddininggo of ft htheet htrhereeeco cmompopuonudnsdasr earpea rptalyrtdlyu edutoe tthoe tphlea npalraintyaroiftyc aorfb ocalirnbeoalinnde panhden pohliecnOolHic gOrHou gprso[u4p5]s. [45]. Additionally, cell studies of tthe combined hiistone deacylase (HDAC) inhibitors 25 and 26 with flfluorouracil, an isosteric repllacement for pyridine against HDAC prottein source (Hela cell nuclear extract), resulted in inhibitory potentials of 5.92 and 2.31 µμM for compounds 25 and 26 compared to the moderate anti-proliferative activity estimated with seven ttumor cellll panells ((K--562,, A549,, U266,, PC--3,, HCT--116,, ES--2,, and HL--7720)) [[46]].. Diis-- covery off tthe essenttiiall rolle off angiiogenesiis iin ttumor progressiion by JJudah Follkman iin tthe llatte 20tth ccentturry hass been rreccenttlly ssupporrtted by many genettiicc and epiidemiiollogiiccall ssttud-- iieess [[4477]].. SSiimiillaarrllyy,, aa ccoombbiinaattiioon ooff deeooxxyy--poodoophyylllloottooxxiin aand 55--flfluoorroourraacciill--yyll sshooweed an increased cytotoxic activity against tumor cell lines compared with the anticancer drugs VP-16 and 5-FU [48]. 4-Deoxypodophyllotoxin-5-fluorouracil, 27, induced cell-cycle arrest in the G2/M phase by regulating levels of cdc2, cyclinB1, and p-cdc2 in A549 cells and migration of A549 cells via down-regulation of matrix metallopeptidase 9 (MMP-9) and up-regulation of tissue inhibitor of metalloproteinase (TIMP-1) [48]. A multi-target inhibitor is also formed by fusing vandetanib 3, a vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor with Vorinostat, 17, an HDAC inhibitor. The fused product, 28 exhibited a very potent inhibitory activity against HDAC with an IC50 of 2.2 nM and strong inhibitory effect against VEGFR-2 at 74 nM [49]. Its inhibitory activity against a human breast cancer cell line MCF-7 Molecules 2021, 26, x FOR PEER REVIEW 6 of 50 an increased cytotoxic activity against tumor cell lines compared with the anticancer drugs VP-16 and 5-FU [48]. 4-Deoxypodophyllotoxin-5-fluorouracil, 27, induced cell-cycle arrest in the G2/M phase by regulating levels of cdc2, cyclinB1, and p-cdc2 in A549 cells and migration of A549 cells via down-regulation of matrix metallopeptidase 9 (MMP-9) and up-regulation of tissue inhibitor of metalloproteinase (TIMP-1) [48]. A multi-target inhibitor is also formed by fusing vandetanib 3, a vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor with Vorinostat, 17, an HDAC inhibitor. The fused product, 28 exhibited a very Molecules 2p0o21t,e2n6,t7 1i3n4hibitory activity against HDAC with an IC50 of 2.2 nM and strong inhibitory effec6to f 48 against VEGFR-2 at 74 nM [49]. Its inhibitory activity against a human breast cancer cell line MCF-7 was at IC50 of 0.85 μM [49]. Arylation of piperlongumine, an amide alkaloid present in Piper lonwgausmat, IPCi5p0eorf g0u.8i5neµeMns[e4 9a]n. dA roytlahteiorn Poifpperip seprleocnigeusm, winiet,ha ncoammibdreeasltkaatlionid Ap4re asef-nt in Piper longum, Piper guineense and other Piper species, with combrestatin A4 afforded a forded a potent speomtein-tsysenmthi-seytnicth aetnicda nhdyhbyrbirdid ccoommppoouundndK SKS-S9,S2-99,,w 2h9ic, hwexhhiicbhit eedxinhcirbeiatseedd riena-ctive creased reactive oxoyxgygeenn ssubsttrraatete(R (ORSO) Sg)e ngeernateiorna,tituobnu, ltinubdueplionly dmeepriozalytimone, rainzdaGti2o/nM, acneldl c Gyc2le/Mph ase cell cycle phase blobclokc k[5[500]].. Figure 4. FEixguarme p4.leEsx aomf pslyesnothf seysniztheedsi zmedulmtiu-tltai-rtgaregte at nantitcicaancerrN N-b-basaesdehde theerotecyrcolcicyccolmicp cooumndpso. unds. The association bTehtewaesesnoc iiantifolanmbemtwaetieonni naflnamd mtuatmioonra npdrotugmreosrsipornog reexsesimonpelixfeimedp lbifiye dinb-y in- flammatory bowel diseases, bronchitis and prostatitis has reshaped the focus of many flammatory bowela dntiisceaancseersd, rburgodnecshigitnisp raongdra mprsofrsotmatistiinsg hleatsa rrgeestihnagptoewda trhdes tfhoecuusse ooff mmualnti-yta argne-ting- ticancer drug desigdinre pctreodglrigaamnds sf.roOmf t hseinsgevlen ttaeregnentitnrogg teonw-coanrtdaisn tinhge huester ocfy mcliuc lctoi-mtaproguentdins g22-–38, directed ligands. Ofofu rthofet hseemve(3n0t,e3e1n, 3n2,itarnodg3e3n) -wcohincthaainrein1,g2, 3h-tertiaezroolceydcelriicv actoivmesp, wouernedpso t2en2t–a3g8a, inst four of them (30, 3c1y,c l3o2o,x aygnedn a3s3e)-2 w(ChOicXh-2 a) raen d1,125,-3ly-ptroixayzgoelnea sdeesr(i1v5a-LtiOvXe)sa, twsuebr-em picortoemnotl aargaanidnsmt icro cyclooxygenase-2 (mCoOlaXr c-2on) caenndtr a1t5io-nlys,proesxpyegcteivnealsy,ews i(t1h5o-Lnly 31 and 33 showing activity against tumorassociated carbonic anhydrase enzymes [51].OX) at sub-micromolar and micro molar concentrations, Dreesspiteectthive efelwy, pwyriitdha zoinnelsyf o3u1n dainndn a3tu3r es,hroecwenitndge macotnisvtriatyti oangoafipnostte ntcuymcoourp led associated carboniwc iathnhloywdtroaxsicei teynhzayvme geesn e[5ra1t]e.d interest within the scientific community. An example is the VEGFR inhibitor vatalanib, 34, which is currently in clinical trials [52]. Investigating the effects of aryl group substitution on the 1,2,4-triazolo core, Romero and coworkers Molecules 2021, 26, 7134 7 of 48 reported that four compounds 35–38 (Figure 4) exhibited good IC50 activities against breast cancer cells below 12 µM [53]. In contrast to the breast cancer cell lines, lung carcinoma cells A549 were resistant with only 35, 36, and 38 being moderately cytotoxic (13.98 to 20.40 µM). However, 36 and 37 exhibited moderate anticancer activities against breast MCF-7 and SKBr3 carcinomas with bioactivities of 5.55 (36) and 11.13 µM (37) for MCF-7 and 5.85 (36) and 8.48 µM (38) for SKBr3. While compound 35 showed moderate anticancer activity (8.58 µM), compound 36 exhibited strong anticancer activity against HeLa cell line at 0.54 µM [53]. Structural extrapolations identified 3-nitrosubstitution on the aryl ring to be the most convenient pharmacophore with strong affinity towards EGFR tyrosine kinase enzyme [53]. A number of biologically active molecules with imidazole and benzimidazole nu- clei have been explored for their diverse therapeutic uses including, but not limited to anti-parasitic, antimicrobial, antiviral, anti-helminthic, anti-hypertensive, analgesic, anti- inflammatory, anti-ulcer, antiallergic applications [54]. Romero-Castro et al., 2011 syn- thesized six novel 2-aryl-5(6)-nitro-1H-benzimidazole derivatives (39–44) (Figure 5) and observed that the cytotoxicity of these compounds against various cancer cells was en- hanced by the introduction of a nitro group at position 2 or 3 of the phenyl ring [55]. Among the derivatives, compound 44 was the most cytotoxic agent against all the cancer cell lines displaying an IC50 less than 10 µM. Interestingly, the same compound 44 was less cytotoxic against the non-neoplastic HACAT cell line. The mode of action exhibited by these compounds involves growth suppression via PARP inhibition, attenuation of DNA replication followed by S phase cell cycle arrest resulting in apoptosis [55]. Similarly, evalu- ation of the activity of the benzimidazole derivative 45 against Hep3B-SR and HuH7-SR cell lines revealed that at 25 µM, it exhibited potent antiproliferative effects on the two cell lines [56]. It perpetuates its mode of action by inhibiting AKT, STAT3, and PARP as well as downregulating Fas, at the cell surface [56]. In another study, novel amidino 2-substituted benzimidazole derivatives linked to 1,4-disubstituted 1,2,3-triazoles by phenoxy methyl or ethyl linkers were synthesized [57]. An in vitro antiproliferative screening of the series revealed that compounds 46 and 47 were the most potent against the cell lines displaying an IC50 in the micromolar range [57]. SAR study revealed that introduction of isopropyl and phenoxymethyl groups at C-5 of the benzimidazole ring enhanced the antitumor activity of the derivative. These novel compounds inhibited protein kinases including TGM2, CDK9, SK1, and p38 MAPK [57]. Benzimidazole–quinolinone is another class of N-based heterocycles that has attracted a lot of interest from medicinal and synthetic organic chemists possibly due to the presence of benzimidazole and quinolinone moieties [58]. An in vitro study evaluated twenty novel benzimidazole–quinolinone derivatives against HepG2, SKOV3, NCl-H460, and BEL-7404 cancer cell lines as well as HL-7702 normal liver cell line [59]. Two of the compounds, 48 and 49 displayed strong potency against HepG2 and BEL-7404 cell lines with IC50 values of 8.45 and 9.06 µM, respectively, by not only inhibiting CDK and PARP but also activating p53 protein, caspase-3 and 9 as well as upregulating of Bax [59]. Cinnamic acids are natural products known for their wide pharmacological activi- ties [60]. Employing the pharmacophore-based design approach, a new hybrid 50 was synthesized from imidazole and cinnamic acid and its activity evaluated against lung and breast cancer cell lines [61]. In addition to inhibiting tubulin polymerization and arresting G2/M phase of the cell cycle, the compound displayed its cytotoxicity against all the cell lines with IC50 in the range of 0.25 to 1.5 µM [61]. Using a similar approach, Li et al. synthesized a series of imidazole derivatives of dehydroabietic acid and found them to exhibit antitumor activities via cell cycle arrest at the S phase, activation of intracellular ROS and decrease in mitochondrion potential leading to apoptosis [62]. Among the series, compound 51 exhibited the highest activity against MCF-7 (0.87 µM), HeLa (9.39 µM), and HepG2 cell lines (8.31 µM) [62]. Molecules 2021, 26, 7134 8 of 48 Molecules 2021, 26, x FOR PEER REVIEW 9 of 50 Figure 5. Examples of synthesized imidazole and benzimidazole multi-target anticancer compounds.. RLei ceetpatlo.,r stcyrreoesninede kaincalusestse (rRoTfKb)e pnlzaiyms iad carziotilcealc oromlep ionu tnhde sdaegvaelionpstmrencet patnodr ptyrorogsrienses okfin caasnecienrvso. lIvtse dinihnibviatsiocunl ahrassp breoeunti nfoguanndd tfoo ustnodpt wtraonnsofovreml ianthioibni,t oprrso5li2fearnadtio5n3 ,w mitihgrsatrtoionng, dmifufletrie-tnatrigaetitoinng, apnodte mnteiatalsstaagsaisi nosft ecastnicmera tceedllgs.l oTmoe irmulparrofivlet rtahtieo neffriactaecy(E oGfF AR)b,bvoatst’csu lLair- nenifdaontihbe, l6ia1l Sghrio wett ahl.f arcetpoorr(tVedE Ga FdRia) raynld-uprelaat ewleitt-hd iesroivxeadzoglr[3o,w4-tbh]pfaycrtiodrisn(eP-D3-GamFRin)od-edpeircitvead- tbiyvea 6p2o pwtoitshi sinahnidbictieolln cpyoctleenatriarelss toaf t4G n0M/G, 31 nsMtag, ean[d63 8]. nFMol laogwaiinnsgt tfhmesir reelaartleiedr rseuccecpetsosr, ttyhreoyssinyen thkiensaizseed 31 -(sFuLbTst3i)t,u tkeidn-a2s-ea riynlismeritd adzoomleasinan rdecteesptteodr th(KemDRa)g, aainnsdt spelvaetnelceat-ndceerrivceeldl glirnoews t[h64 f]a. cOtofra lrletcheepitmori dbaeztoal e(sPsDyGnFthRe-sβi)z,e dre,scpoemctpivoeulnyd[6594,7e0x].h Iinbi taendotthheerh isgthuedsyt, pJointefnencyg Wagaanings tanaldl tchoe-wceolrlklienres sdwisictohvIeCr5e0dl etwssot htrainpl2e0 i0nhniMbit[i6o4n] .cIhnetmeroestytipnegsl,y ,6c3o amnpdo 6u4n (dFi5g5uwrei t6h) farnom-O sHcregeronuinpg ionfs ttehaedseo fco-NmHpo2uansdisn dceormivpedou fnrodm5 4reaalscotiosnh obwetewdegeno obdipphoetneynlc-yaraygl auinresat aHnedL saaalincydlaHldCoTx-i1m5ec e[7ll1l]i.n Tehsewsei tthwIoC d50eroivf a1t0iv0easn sdho2w00edn Mstr,ornesgp peocttievneclyy .aWgahinesnt pSAroR-awngais- opgerefnoircm reecdeopntotrhse (VcoEmGpFoRu-2n,d tsy,riotswinaes koibnsaesrev 2ed (TthIEa-t2w), hainled tehpehardind ittyiopne oBf raenceaprtoomr a(EtipchriBn4g) roensuthlteinimg iidna tzhoel einrihnigbiitmiopnr oovf eedndthoethaenlitaipl rcoellilf esruartviviveaelf,f vecatssc,uthlaer pplearcmemeaebnitliotfy,a nmaiglirpahtiaotnic, agnrodu pproonliftehreatiimonid [a7z1o]l.e nitrogen and the replacement of the imidazole ring with an ester or amide caused a loss in activity [64]. The novel imidazole derivatives inhibit microtubules Molecules 2021, 26, 7134 9 of 48 disrupting the formation of mitotic spindles which in turn causes cell cycle arrest and apoptotic cell death [64]. In an attempt to improve efficacy and overcome multidrug resistance, Bai et al. re- ported the imidazole derivatives 54, 55 and 56. Compound 56 was similar to 54, but had an electron withdrawing group (carbonyl group) attached to the imidazole ring [65]. They reported that compound 56 targeted tubulin and DNA by disrupting microtubule assem- bly, causing DNA damage, and inducing cell cycle arrest. In addition, 56 mediated ROS mitochondrial and apoptotic pathways with IC50 of 27.42, 23.12, and 33.14 nM against SW480, HCT-116, and Caco2 cell lines, respectively [65]. Building on a bioactive ingredient (ligustrazine) from widely used Chinese herbs, Zha et al. profiled the potentials of thirty-two derivatized ligustrazine frameworks against five cancer cell types, namely, tubulin, EGFR, tyrosine receptor kinase (TRK), kafirin (KAF), and B-raf proto-oncogene (BRAF) [66]. Among the synthetic candidates only two, 57 and 58 Molecules 2021, 26, x FOR PEER REVI(EFWig ure 6), exhibited potency as multi-target anticancer inhibitors to Tubulin, EGFR1,0K oAf 5F0 and BRAF and tropomyosin receptor kinase (TRK) as well as modulators of multidrug regulators (MDR) [66]. Figure 6. Derivatives of lliigusttrrazziinee ((5577,,5588)),, 55--aamiinnoo--44--ppyyrrimimididininooll( 5(599),),N N-(-2(2-a-ammininoopphhenenyyl)l)b benenzazmamidide ea carcirdiidniene(6 (06)0, )L, iLnii-- fnainfaibni(b6 1(6) 1a)n adnidts iitsso ixsaozxoalz[o3,l4[3-b,4]-pby]rpiydrinidei-n3e-a-3m-ainmoi-ndoe-rdivearitvivaetiv62e, 6a2s, wase lwl aesllo atsh eorthbeipr hbeipnhyel-nayryl-lauryrel audreear idvaetriivveat(i6v3e a(n6d3 a6n4)d. 64). A demonstration of weak in vitro/in vivo activity by a hit compound is often exploited 2in.1.t2h.e Nsaetluecratilo Pnrodf uacntsi nfritoimal Vscaarfifoulds Soorusrtcaerst ing material for the synthesis of improved bioacTtihvee mcoemdpicoinuanld us.seE mofp nloaytuinragl tphrisodapupctrso adcaht,eFs atroa agnectieanl.ts tyimntehse s[i7z2e,d73s]e. vCeunrdreenritvlya,t iivt eiss eosfti5m-aamteidn oth-4a-tp aybroimuti d7i0n%o loof fnwewh idchrucgosm fopro tuhned tr5e9atsmhoenwt eodf binrfoeacdtiosupse cdtirsuemaseasn otir-icgainncaeter dacirteivcittlyy, owri itnhdtihreecintldy ifcraotmed npaetrucreanl tpagroedinuhctisb iotfio bnostho ffltohreaflo alnlodw fianugncaal nocreigrsin: sh e[7m4a,7t5o]l.o Ogivcearl t(h84e. 1y%ea)r,sc othloenre(7 h2a,1v5e% b)e,eCnN sSev(6e6r.a3l4 r%ev),imewelsa onno mplaa(n6t6s. 4a8s% re),aol vaanrdia pno(t5e1n.5ti5a%l )s,oruerncaels( 5o5f. 9c5o%m)-, pporousntdatse a(n6d1. 8th5e%ir) ,uasned inb rtehaes ttr(e6a0t.m87e%nt) o[6f 7c]a.n(cNer-(. 2P-arommininoepnhte anmylo)nbge nthzeasme irdeeviaecwrisd iins ethies panroocteheedr icnhgesm ooft ythpee 1w6htho saendneuraivl amtieveetsinhga voef bteheen Sfoocuinetdy tfoosrh Eocwonimomprioc vBeodtasnuyic: id19a7l 5a c[t7io6n]. Conantcuemr otrrecaetlmlse[n6t8 ]h.aHs obweneevfeitre, do fitmhemeelnesveelny nfroovmel nsyantuthraelt icprNo-dhuecttesr.o Pcyroclmicinmeanct roamcyocnligc tdheersive aatrive etshtee vstiendca( Failgkualroei6d)so fnrolymc oCmatphoaruanndth6u0s proossesuess s(eVdinmcau rltois-etaar) guesteindg fporo ttehnet itarleaagtmaiennstt oHfD leAuCke(m87ian aMn)d, tTraanxosml fermombr Tanaxeulsig baanccda-taac tthivaatt iesd urseecde pfotorr tthyer otrseinatemkeinnat soef (cFeLrTv3ic)a(l8 c7annMce)r, [77,78]. The search for multitarget anticancer compounds can therefore not be complete without considering natural products from plant, soil, marine, fungal, and animal sources. 2.1.3. Nitrogen-Heterocyclic Natural Products with Multitarget Inhibitory Properties The properties of some natural products have also been harnessed in the search for improved anticancer activities (Figure 7), For example, berberine 65, isolated from Rhi- zoma Coptidis is a heterocyclic alkaloid known to have multi-targeting potentials against a myriad of human cancer receptors [79]. It suppresses growth of cholangiocarcinoma cell lines. This anticancer activity has been attributed to inhibitions of ERK1/2, NF-κB and STAT3 pathways. The compound also arrests the G1 cell cycle at 9.3 μM concentration within 48 h and 3.0 μM within 72 h [80]. Despite the DNA intercalation property of ber- berine 65 Lin and co-workers evaluated it on N-acetyltransferase (NAT) suppression in HL-60 cells and observed no effects on its gene expression at 30 μM [81]. Evodiamine, 66, isolated from Evodia rutaecarpa, has been described as a tumor inhib- itor with multi-targeting profiles against Topoisomerase I and II. Though the in vitro ac- tivity was encouraging, it demonstrated low in vivo potency [82]. Xinglin Li and co- Molecules 2021, 26, 7134 10 of 48 and Janus kinase 2 (JAK2) (0.68 µM), with a high cytotoxic effect on human acute myeloid leukemia cell line MV4-11 and human erythroleukemia (HEL) cells. Compound 60 acts by halting cell proliferation (IC50 0.12–0.35 µM) triggered by G0/G1 cell cycle arrest and cellular apoptosis by inhibition of Topoisomerase 1 and HDAC [55]. (N-(2-aminophenyl) benzamide acridine is another chemotype whose derivatives have been found to show improved suicidal action on tumor cells [68]. Receptor tyrosine kinases (RTK) plays a critical role in the development and progress of cancers. Its inhibition has been found to stop transformation, proliferation, migration, differentiation, and metastasis of cancer cells. To improve the efficacy of Abbott’s Linifanib, 61 Shi et al. reported a diaryl-urea with isoxazol[3,4-b]pyridine-3-amino-derivative 62 with inhibition potentials of 4 nM, 3 nM, and 8 nM against fms related receptor tyrosine kinase 3 (FLT3), kinase insert domain receptor (KDR), and platelet-derived growth factor receptor beta (PDGFR-β), respectively [69,70]. In another study, Jinfeng Wang and co-workers discovered two triple inhibition chemotypes, 63 and 64 (Figure 6) from screening of these compounds derived from reaction between biphenyl-aryl urea and salicylaldoxime [71]. These two derivatives showed strong potency against pro-angiogenic receptors (VEGFR-2, tyrosine kinase 2 (TIE-2), and ephrin type B receptor (EphB4) resulting in the inhibition of endothelial cell survival, vascular permeability, migration, and proliferation [71]. 2.1.2. Natural Products from Various Sources The medicinal use of natural products dates to ancient times [72,73]. Currently, it is estimated that about 70% of new drugs for the treatment of infectious diseases originate di- rectly or indirectly from natural products of both floral and faunal origins [74,75]. Over the years there have been several reviews on plants as real and potential sources of compounds and their use in the treatment of cancer. Prominent among these reviews is the proceedings of the 16th annual meeting of the Society for Economic Botany: 1975 [76]. Cancer treatment has benefited immensely from natural products. Prominent among these are the vinca alkaloids from Catharanthus roseus (Vinca rosea) used for the treatment of leukemia and Taxol from Taxus baccata that is used for the treatment of cervical cancer [77,78]. The search for multitarget anticancer compounds can therefore not be complete without considering natural products from plant, soil, marine, fungal, and animal sources. 2.1.3. Nitrogen-Heterocyclic Natural Products with Multitarget Inhibitory Properties The properties of some natural products have also been harnessed in the search for improved anticancer activities (Figure 7), For example, berberine 65, isolated from Rhizoma Coptidis is a heterocyclic alkaloid known to have multi-targeting potentials against a myriad of human cancer receptors [79]. It suppresses growth of cholangiocarcinoma cell lines. This anticancer activity has been attributed to inhibitions of ERK1/2, NF-κB and STAT3 pathways. The compound also arrests the G1 cell cycle at 9.3 µM concentration within 48 h and 3.0 µM within 72 h [80]. Despite the DNA intercalation property of berberine 65 Lin and co-workers evaluated it on N-acetyltransferase (NAT) suppression in HL-60 cells and observed no effects on its gene expression at 30 µM [81]. Evodiamine, 66, isolated from Evodia rutaecarpa, has been described as a tumor in- hibitor with multi-targeting profiles against Topoisomerase I and II. Though the in vitro activity was encouraging, it demonstrated low in vivo potency [82]. Xinglin Li and co- workers have reported improved in vivo antitumor activity in a series of novel boron- incorporated derivatives of evodiamine 66 using HCT116, MCF-7, and A549 cell lines [83]. The N13 deprotected phenyl boronic acid derivative, 67 showed excellent antitumor ac- tivity in an HCT116 xenograft model in mice (IC50 of 16 nM) disrupting the PI3K/AKT signaling pathway [83]. Molecules 2021, 26, x FOR PEER REVIEW 11 of 50 workers have reported improved in vivo antitumor activity in a series of novel boron- incorporated derivatives of evodiamine 66 using HCT116, MCF-7, and A549 cell lines [83]. The N13 deprotected phenyl boronic acid derivative, 67 showed excellent antitumor ac- Molecules 20t2i1v, 2i6t,y7 1i3n4 an HCT116 xenograft model in mice (IC50 of 16 nM) disrupting the PI3K/A1K1Tof 48 signaling pathway [83]. Figure 7F.i gNu-rhee7t.eNr-ohceytecrloiccy nclaictunraatul rpalrpordoudcutc tccoomppoouunndds sw withitmhu mltiu-tlatrig-teat regffeect tesfofnecctasn coenr cceallns.cer cells. Some naturally occurring mangrove indolocarbazoles were investigated for their Some naturamlluylt iopcleckuirnraisnegi nmhibaintigonropvoete nintidaloalgoacianrsbt naozno-lsems awll-ceerlel luinngvecsatnicgeartceedll s.foCro mthpeoiurn d multiple kinase i6n8hdibeimtionns tpraotetednsteilaelc taivgiatyintostw narodns-osmncaopllr-octeeliln sluHnEgR c2a(nICce50r 1c9e0l.l7s.n CMo),mHpEoRu3n(IdC 50 68 demonstrated 1s6e0l.e3cntMiv)i,tayn tdoHwEaRr4d,s( IoCn50c1o8p0r.1onteMin) s[8 H4].EIRt i2n d(IuCce5d0 1a9p0o.p7t onsMis a)n, dHeExRer3te (dICa 5s0y 1n6er0g.i3s tic nM), and HER4, (eIfCfect 1b8y0c.o1m nbMin)i n[g84w].i tIht ciinsdpluatciendin aNpoCpI-toHs1i9s7 a5ncdel les.xeIt50 rtaelsdo ap ostyenntelyrgainsdticse elefcfeticvte ly by combining witinhhcon c ib sits itpedruclta g eti rnow inth NofCnIa-t uHra1l9ly7o5c ccuerlrlsin. gItn aolns-osm paollt-ecenltlllyu nagncda rscinoma (NSCLC) cells andd NIH-3T3 cells. Evaluation of the in vivo performanceerleevcetailvedeltyh aitn6h8iibnihtiebdit ed growth of naturaElGlyF Ro-Lcc85u8rRri/nTg7 9n0Monw-sitmh aICll5-0coefll2 7l9u.6nngM caanrcdinRoEmT (aIC (5N0 1S8C3.L7 CnM) )c[e8l4l]s. Iannad dcitoionn- to structed NIH-3T3th ceepllost.e nEcvyaolfu6a8taiogani nosft thees einta rvgievtso, ipt aelrsfoodrimspalanyceed rdeovwenarleegdu ltahtiaotn 6o8f pihnohsipbhioter-dA kt EGFR-L858R/T79a0nMd pwhoitshp hIoCr5-0E oRfK 2[7849]..6 nM and RET (IC50 183.7 nM) [84]. In addition to the potency of 68 against Lthyceospeo tdairngee, t6s9,,have anticancer effec i t tt h aelsmoa dinisaplklaalyoeiddo dfoLwycnoproedgiuumlactliaovnat uomf pehxtorascpthwoars-Areporton HeLa cells through DNA damage, 5-LOX inhibitiokn,t Gan ed 0/dG to 1 phosphor-ERK [8c4e]l.l cycle arrest, deactivation of oxidation resistance (OXR) receptor and mitochondrion Lycopodine,m 6e9m, btrhaen emdaepino larlikzatliooind [8o5f] .LJy.cRopobodleisuamn dclcaov-awtuormke resxitdraencti fiwedasm raexpimoristceidn 7t0o as have anticancer epfofescset sosinn gHmeuLlati tcaergllest tahnrtiocuangcher DpNroApe rdtiaems [a86g]e. ,T 5h-eLyOinXv eisnthigiabtietdioitns, aGct0iv/iGty1a cgealiln st cycle arrest, deactciavnacteirocne lol lfi noexsiidnavtiitoron arnedsiisntaanxcene o(gOraXftRm) oreucseepmtoodre al nofdm meliatnoocmhoananddrifoonun mdethmat-70 inhibited proliferation of all of the following five triple-negative breast cancer cell lines brane depolarizataitotnh e[8st5a]t.e Jd. RICoblveasl uaensd: M coD-Aw-MorBk-e46rs8 i(d0.e6nµtMif)i,eMd DmAa-xMimB-i2s3c1in(3 790µ Mas) ,pMosDsAes-Msi50 Bn-g4 53 multitarget antic(a1n5cµeMr )p, HroCpCe-r7t0ie(6s0 [µ8M6])., aTnhdeByT -i5n4v9 e(1s5tiµgMat)e[d86 ]i.tsIt iascstuivggiteys teadgtahiantstth ecamneccehra ncisemll of lines in vitro anda cinti oan xoef nthoegcroamftp omuonudsinev molvoedsetlh eofin mduecltaionnoomf aD NanAdd afomuangeda tshtahte 7p0ri minahryibsiutiecdid al proliferation of alalc otifo nthaes fwoelllloaws ainctgiv faitvioen torfipDlNe-Anedgamataigvee rbesrpeoansste cpaantchewra cyeslaln ldinceesll acyt ctlheea rsrteastte[d86 ]. IC values: MDA-MBDidemnins are depsipeptides isolated from the sea squirt. They possess activity50 agains-t46v8ar (io0u.6s μcaMnc)e,r Ms iDncAlu-dMinBg-P233818 (l3y9m μphMoc)y, tMicDleAuk-eMmBia-4a5n3d (B1156 μmMel)a,n HomCaC[-87]. 70 (60 μM), and BDTid-e5m49n i(n15B ,μ71Mis) r[e8p6o]r. tIetd itso stuargggeet sDtNedA tfhuantc ttihonea mlityec[h88a]n. iIstmpe rotfu rabcsticoelnl- coyfc ltehaen d compound involvinehsi bthitse tihnedsyunctthioesnis oof DNAAa tdtahme ealogneg atsio tnhpeh parseimviartyh esduuicaildinahli baictitoionno fapsa wlmeitlol yl- as activation of DpNroAte idnathmioaegstee rraesesp1o(PnPsTe1 p) aantdhweuakyarsy oatnicdt rcaenlsll actyiocnlee loanrrgeastito n[8f6ac].t or-1α (EEF1A1) [89]. Didemnins aItrael sdoeapctsivipateepstciadsepsa siesso, lthateeredb yfrinodmu citnhge aspeoap tossqius iarntd. iTnhheibyit spporsosteeisns syanctthivesitisyb y preventing eukaryotic elongation factor (Eef-2)-dependent translocation (Figure 8) [90]. against various cancers including P388 lymphocytic leukemia and B16 melanoma [87]. Didemnin B, 71 is reported to target DNA functionality [88]. It perturbs cell-cycle and inhibits the synthesis of DNA at the elongation phase via the dual inhibition of palmitoyl- protein thioesterase 1 (PPT1) and eukaryotic translation elongation factor-1α (EEF1A1) Molecules 2021, 26, x FOR PEER REVIEW 12 of 50 Molecules 2021, 26, 7134 [89]. It also activates caspases, thereby inducing apoptosis and inhibits protein syn1t2hoefs4i8s by preventing eukaryotic elongation factor (Eef-2)-dependent translocation (Figure 8) [90]. Fiigurre 8.. Chemiiccall ssttrrucctturress off Diidemniin B,, 71 and Ovotthiiollss,, 72 wiitth a ssummarry off ttheiirr biiollogiiccall accttiiviitty ttowarrdss sseelleecctteedd ttaarrggeettss.. Compound 7722i sisa nanex aemxapmlepolef aogf rao ugprouf phi sotifd hiniset-ideirniev-edderciovmedp ocuonmdps ocaulnledds Ocvaloltehd- Oiovlso.tThhioelse. Tcohmespeo cuonmdpsoaurendfosu anrde fionumndos itnm memosbt emrsemofbtehres koifn tghdeo kminPgrdootomct iPstraot(oecstpisetcai a(ellsy- palegcaiaellayn adlgpareo taonzdo ap)roastowzoeall) aass mwaenlly asm marainye minavreirnte binravtersteinbcrlautedsi ningcPluadraincegn Ptraortaucsenlitvriodtuss, lSivtriodnugs,y lSotcreonntgroytluocsepnutroptursa tpuusr,pAurbataucisa, lAixrubalac,iaM liaxruthla,s tMeraiartshgalsatceirailais ,gAlasctiraolpise,c tAenstraoupreacntetina cauus-, Oracnttoiapcuussv, uOlcgtaorpisu,sL voulilgoarvisu, lLgaorligsoa vnudlgPalraitsy annedre iPsladtuymnereiliisi d[9u1m].erCilioi m[9p1o].u Cnodm7p2oeuxnhdib 7it2s eixts- hanibtitcsa nitcse arnptircoapnecretire psrboypienrhtiiebsi tbiny ginahuitboiptihnagg ayuitnoiptihaatigoyn i[n9i2ti]a. tion [92]. The miiccrrosscclleerrooddeerrmiinnss aarree cycyclcilci chehxeaxpaeppetpidtiedse fsrofrmom a daedepee-wp-awteart seprosnpgoen ogfe tohfe tghee- nguens uMs iMcriocsrcolsecrloedroerdmeram [a9[39]3. ]T.hTehye ywwerer efirfisrts trerpepoortretded bbyy GGuuzzmmaann eett aall..,, durriing ttheiir questt fforr ssmallll molleeccullee iinhiibbiittoorrssa aggaaiinnssttn nuuccleleaarrf afactcotorrk kapappaaB B( N(NF-Fκ-Bκ)Bc) eclelsll[s9 [49]4. ]M. Micircorsocslecrleo-- rdoedrmerimn iAn ,A73, 7a3n danBd, 7B4, in74h iibniht iNbiFt- κNBFt-rκaBn stcrrainpstciorinpatlioanctailv iatcytilveaitdyi nlegatdoinregd tuoc trieodnuocftiloenve olsf loefvpehlso ospf hpohroyslpahteodry(alactteivde ()aNctFiv-κeB) NinFt-hκeB Ains PthCe- 1AcsePlCl l-i1n ec,elalg lainines, tatghaeinAsst PthCe- 1A, sBPxCP-C1-,3 B, xMPICA- 3P,a MCaIA-2 PaanCdaP-2A aNnCd- P1ApNanCc-r1e aptaicnccarenacteicr ccealnlcleinr ecse,lla lnindeisn, dauncde isnidguncifie csaignnt iafpicoapntto aspisoipntothsies Ains PthCe- 1A, BsPxCPC-1-,3 BaxnPdCth-3e aPnAdN tCh-e1 PceAllNliCne-1s [c9e4l]l. lSinuebss e[q9u4]e.n Stuinbvseeqstuigeantti oinnvoefstthigeamtieocnh aonf itshme mofeacchtaionnismof o73f aacntidon74 orfe 7v3e aanledd 7t4h aretvtheaelyedal tshoarte tghuelya taeldsot hreegeuxlaptreeds stihoen eoxfpprerossteioinns oifn ptrhoe- tgeliyncso igne nthsey gnltyhcaosgeekni nsyasneth3apsea tkhiwnaasye (3F ipgautrhew9a)y[9 (4F]i.gure 9) [94]. Aaptamines, 75 are a group of bioactive benzo[de[1,6]]-naphthyridine alkaloids, iso- lated from marine sponges mostly belonging to the genus Aaptos [95]. Aaptamine, 75, possesses antioxidative, antimicrobial, antifungal, and antiretroviral activity. It is also reported to modulate AP-1, NF-κB, and p53-dependent transcriptional activity in JB6 Cl41 cells (Figure 10) [96]. Neoechinulin A, 76 is from the marine fungal strains Microsporum sp and Aspergillus sp [97]. It consists of three structural moieties: an indole, a diketopiperazine and an isoprenyl group. Cytotoxicity tests of 76 on human cervical carcinoma HeLa cells showed it to express p53, p21, Bax, Bcl-2, Caspase 9, and Caspase 3 proteins [98]. Western blot analysis also revealed that 76 could induce cell apoptosis through down-regulation of Bcl-2 expression, up-regulation of Bax expression and activation of the caspase-3 pathway [97,98]. Compound 76 also suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2) and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) [97]. Furthermore, 76 decreased the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) [97]. It also blocks the Molecules 2021, 26, x FOR PEER REVIEW 13 of 50 Molecules 2021, 26, 7134 13 of 48 Molecules 2021, 26, x FOR PEER REVaIcEtWiv ation of nuclear factor-kappa B (NF-κB) in LPS-stimulated RAW264.7 macrophages by 13 of 50 inhibiting the phosphorylation and degradation of inhibitor kappa B (IκB)-α. Moreover, 76 decreased p38 mitogen-activated protein kinase (MAPK) phosphorylation (Figure 11) [97]. Figure 9. Chemical structures of Microsclerodermin A and B with a summary of their biological activity towards selected cancer targets. Aaptamines, 75 are a group of bioactive benzo[de[1,6]]-naphthyridine alkaloids, iso- lated from marine sponges mostly belonging to the genus Aaptos [95]. Aaptamine, 75, pos- sesses antioxidative, antimicrobial, antifungal, and antiretroviral activity. It is also re- FpFigiougrruteer9ed. 9Ct.o hC ehmeoimcdailucslatalr tusect trAurcPets-u1or,fe NsM oFicf-r κoMsBci,lc eraroonsdcel erpmro5id3n-eAdrmeapninde nABd weaninthdt taBrsa uwnmsitcmhr aiapr ytsiuofmnthamel airarcybti iovlfoi gttyhice aiilnr bJBio6lo Cgilc4a1l acatecivtlilivsty i(ttyFo iwtgoauwrrdaesr ds1es0l e)sc e[tl9eed6c]tc.ea dnc cearntacregre ttas.rgets. Aaptamines, 75 are a group of bioactive benzo[de[1,6]]-naphthyridine alkaloids, iso- lated from marine sponges mostly belonging to the genus Aaptos [95]. Aaptamine, 75, pos- sesses antioxidative, antimicrobial, antifungal, and antiretroviral activity. It is also re- ported to modulate AP-1, NF-κB, and p53-dependent transcriptional activity in JB6 Cl41 cells (Figure 10) [96]. FFigiugruere1 01.0.C Chheemmiciaclals tsrturcutcutrueroe fotfh teheb ebneznoz[do[ed[1e, 6[]1],-6n]a]p-nhathpyhrtihdiynreidailnkea laolikdaAloaipdt aAmaipnteamwinthe awith a sum- summamrya royf oitfsi tbsiboilolgoigciacal laaccttiiviity towaarrddsss esleelcetcetdedca ncacenrctearr gtaertsg.ets. PiNpeeroloencghuimniunlein(P LA),, 7776i sisan fraommid ethalek amloaidriinsoela ftuednfgroaml sltornaginpsep Mpeirc(rPoispperorlounmgu smp La.)n[d99 A]. spergillus Co bsrp m e [ p as9 o t7 u c]a. n nI d ct 7 ec 7 r,o innduces tansdistlesu okf h ethdreeaeth storfuncutmurearol ums ocaientcieersc: eallnli ninesdionlcel,u ad idnigkpetancreatic cancer,emia [100,101]. The compound is one of several aompiidpeeraalkzainloei dasnd an iso- frpormentyhle ggreonuups .P Cipyetrotthoaxtihcaitvye tbeesetsn ofof u7n6d otno hpuosmseasns acnertivciacnacle craarcctiinviotmiesaa HmeoLnag coethllesr showed it btFiooig leouxgrpiec ra1el0s.as Cc pthiv5ei3mt,i eipcsa2[l1 9s,9t rB,1ua0cx1tu], .rBePc oilp-f2 et,rh lCeo nabsgepnuzamosi[end 9e, r[ a1a,np6di]d] -lCnyaaipsnphdtauhscyeer si3d tpihnreeo dateelkaianthlso io[d9f 8Ah]ua. pmWtaemnstipenarenn w- biltho ta a snuaml-- cyrmesaitsriy ca oclsaf onit csre ebrvicoelalollgseimdca alti hancalytti vt7hi6try o ctuoguwhladtrh diensi dsneduleuccectt eicoden lclao naf pcfeorrpr toatporgtsoeistis st. h[1r0o1u].gPhL ddoiwrecnt-lyrebgiundlastiton of Bcl-2 aenxdpirnehsisbiiotsnt,h ue pan-rteiogxuidlatniot enn zoyfm Bea,xg luetxapthreiosnsieoSn- traanndsf earcatsievPaiti1o,nre souf lttihneg icnaeslpevasaete-d3 pathway [97,98N].e oCeocmhipnouulinnd A 7,6 7 6a lisso f rsoumpp trhees smedar tihne fpurnogdaulc sttiroani nosf Mniitcrriocs pooxriudme (sNp Oan)d a nAdsp pergoislltuas- gspla [n9d7i]n. IEt 2c o(nPsGisEt2s )o afn tdh rtehee setrxupcrteusrsaiol nm ofi eintidesu: caibnl ein ndiotrliec, oax didikee stoypnitphearsaez (iinNeO aSn)d a annd icsyo- cplroeonxyylg gernoauspe-. 2C y(tCotOoXxi-c2i)t y [t9es7t]s. oFf u76rt hoenr hmuomrea,n c7e6r vdiceaclr cearsceidn omthae HseeLcar ecteilolns shoofw epdro i-t to express p53, p21, Bax, Bcl-2, Caspase 9, and Caspase 3 proteins [98]. Western blot anal- ysis also revealed that 76 could induce cell apoptosis through down-regulation of Bcl-2 expression, up-regulation of Bax expression and activation of the caspase-3 pathway [97,98]. Compound 76 also suppressed the production of nitric oxide (NO) and prosta- glandin E2 (PGE2) and the expression of inducible nitric oxide synthase (iNOS) and cy- clooxygenase-2 (COX-2) [97]. Furthermore, 76 decreased the secretion of pro- Molecules 2021, 26, x FOR PEER REVIEW 14 of 50 Molecules 2021i,n2f6l,a7m134matory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL- 14 of 48 1β) [97]. It also blocks the activation of nuclear factor-kappa B (NF-κB) in LPS-stimulated RAW264.7 macrophages by inhibiting the phosphorylation and degradation of inhibitor kappa B (IκB)-α. iMntroarceeollvuelarr, R7O6 Sdleecvreelas saendd spu3b8s emquiteongt eanpo-apcttoitvicacteeldl dperaothteiinnc kanincearsse. P(ML hAaPs bKe)e n shown phosphorylation t(oFicgauursee c1e1l)l c[y9c7l]e. arrest [99,101]. FigureF1i1g.uCreh e1m1.i cCahl estmruicctaul rsetsruofcttuhreeasm oifd tehael kaamloiiddes aNlkeoaelochidinsu NlineoAecahnidnuPliipne rAlo anngdum Piinpeerwloitnhgaumsuimnem wariytho fat heir biologiscualmamctiavrityy otof wthaerdirs bsieoleloctgeidcacal naccetrivtaitryg ettosw. ards selected cancer targets. Piperlongumine B(Penzand belLo) o n, g7 p7h eisn aannt ahmridineto the benzidylei a allkkaallooiidds iasorelactoemdm froonmly lfoonugn dpeinppPaepr a(Pveipraceae and Rutaceaesoquinoline family. They have been extenesriv loelnygiunmve stigated L.) [99]. Compounfodr 7th7e iinr dmuecdeisc itnhael dpreoapther otife snaunmdebroiouasc tcivaencceorn scteitlul elinntess[ 1in02c]l.udTihnogu gphanthcreey-exhibit a atic cancer, breastv acrainetcyero,f apnhdar lmeuackoelmogiiac a[l1f0u0n,c1t0io1n].s T, ohnel ycothmospeowunithd misu oltnime oodf asleitvyearanlt iacamnicdere activities alkaloids from thea rgeepnruese Pnitpeder itnhtahte hcauvrere bnet erenv fioewu.nd to possess anticancer activities among other biological activiTtihees b[e9n9z,1o0p1h]e. nPainptehrliodningeuamlkianleo idraspairdelyge innedraulclyesi stohlaet eddeafrtohm ofn ahtumralanso urces as pancreatic cancert cheelilrs qmuaatienrlnya trhyroamugmho tnhieu mindsaulctst.ioSna onfg fueirnraorpinteo,si7s8 [h10as1]b. ePeLn disiorelacttelyd bfrionmdst he roots to and inhibits thoef Saanntgiouxiniadraianct aennadzeynmsise,,C ghleulitdaotnhiiuomnem aSj-utsr,aAnrsgfeemraosnee mPei x1ic, arneasausltwinegll ains tehlee-roots and vated intracellulalre aRvOesS olefvZealnst ahonxdy lsuumb(sFeaqguareanxta anpthoopxytolotiidce cs)elzla dntehaotxhy lionid ceasn, Zce. rbsu.n PgLea hnausm baenedn Z. gilletii (Fagara macrophylla). The compound has diverse medicinal properties including anticancer shown to cause ceplrlo cpyecrlteie as.rrAesltth [o9u9g,1h0t1h]e. underlying mechanism of action for Sanguinarine as an anti- Benzophenatnutmhroirdaingeen atliksayleotitdosb aerfeu lcloymelmucoidnaltye dfo, Xuundet ianl. Preappoarvteedratcheaat e7 8acnadu sRedutaaccoenacee ntration- and belong to thed beepneznydle nistoiqnhuiibniotiloineo ffagmrowilyth. TinhHeye Lhaaavned bSeieHna ehxutemnasnivceerlyvi icnalvceasnticgeratweidth foICr 50 values their medicinal proof p2.e4r3tiaensd a3n.d07 bµioMa,crteivspe eccotinvsetliytu[1e0n3t]s. [C1e0l2l ]c.y Tclheoaungalhy stihserye veexahleibdita pao vpatoriseistyin duction of pharmacologicwala fsuanscatiroensusl,t oonfldyo twhnorseeg wuliatthio mn oufltBimcl-o2daanlditNy Fa-nκtBicaanndcearn aucptirvegituielast iaorne opfrBea-x protein Molecules 2021, 2s6e, xn tFeOdR iPnE EtRh eR EcVuIrErWeexn ptr eressviioenw[1. 03]. Sanguinarine is also reported to cause cell cycle obstruction and indu15c eof 50 The benzophaepnopantotshisriodfinhue maalknaploroidstsa taercea rgceinnoemraallcye llissovliaataetdte nfruoamtio nnaotfucryacll insoduerpceensd aesn t kinases their quaternary (aFmigmuroen1i2u)m[10 s4a].lts. Sanguinarine, 78 has been isolated from the roots of Sanguinaria canadensis, Chelidonium majus, Argemone mexicana as well as the roots and leaves of Zanthoxylum(Fagara xanthoxyloides) zanthoxyloides, Z. bungeanum and Z. gilletii (Fagara macrophylla). The compound has diverse medicinal properties including anticancer properties. Although the underlying mechanism of action for Sanguinarine as an anti- tumor agent is yet to be fully elucidated, Xu et al. reported that 78 caused a concentration- dependent inhibition of growth in HeLa and SiHa human cervical cancer with IC50 values of 2.43 and 3.07 μM, respectively [103]. Cell cycle analysis revealed apoptosis induction was as a result of downregulation of Bcl-2 and NF-kB and an upregulation of Bax protein expression [103]. Sanguinarine is also reported to cause cell cycle obstruction and induce apoptosis of human prostate carcinoma cells via attenuation of cyclin dependent kinases FigFuirgeu r1e2(.1F 2Ci.ghCuehmreeimc 1aic2l a)sl t[rs1utr0cut4cu]tru. er eofo fththee qquuaateterrnnaarryy ammonium salltt aallkkaallooiiddS Saanngguuininarairnineew withitha sau smumamryaroyf oitfs ibtsio bloiogliocaglical actaivcittiyvi tyowtoawrdarsd sseslecletcetde dcacnacnecre rtatargrgeetsts. . CChheleelreyryththrirninee 7799,, iissoollaatteedd ffrroom CChheelliiddoonniiuummm maajujus,s,Z Z. x. axnatnhtohxoyxlyoildoeids,esZ, .Zcl.a cvlaahvearhceurlcisu,lis, anadn dZZ. r.hrohiofiofoliluiumm aammoonngg ootthheerrss,, iiss aa ppootteenntt,,s seelelecctitvive,ea, nanddc eclel-lpl-epremrmeaebaleblper optreointekinin kaisneaCse C inihnihbiibtiotor r[1[10055].] .CChheelelerryytthhrriinnee eexxhhiibbiittss iittss aannttiittuummoorrp proropperetriteisesb ybyin ihnihbiibtiintigntgh tehper polriofelirfae-ra- tion of androgen-independent prostate cancer cells DU145 and PC-3 at concentrations of 5 and 10 μM [106]. Western blot analysis revealed that 79 inhibited metastasis of prostate cancer cells by suppressing MMP-2, MMP-9, and uPA and also boosted the expression of endogenous inhibitors TIMP-1 and TIMP-2 as well as plasminogen activator inhibitors (PAI-1 and PAI-2) [106]. In vitro and in vivo studies have also disclosed the effects of 79 on the growth inhibition and apoptosis induction on HEK-293 and SW-839 renal cancer cells [107]. Chelerythrine, 79, also significantly inhibits the phosphorylation of extracellu- lar signal-regulated kinase (ERK) and Akt accompanied by upregulation of p53, and downregulation of Bcl-2, caspase-3, and PARP (Figure 13) [107]. Figure 13. Chemical structure of Chelerythrine with a summary of its biological activity towards selected cancer targets. Nitidine 80 is found mostly in the roots of Zanthoxylum nitidum (Fagara nitida), Z. gil- letii (Fagara macrophylla), Z. tessmanii, and Z. chalybeum (Fagara chalybea). Nitidine was first reported from Z. nitidum in 1958 by Arthur et al. [108]. It was later reported from Z. gilletii (Fagara macrophylla) by Torto and Addae-Mensah in 1970, Wall et al. in 1971, and Fish and Waterman in 1972 [109–112]. Since then, it has been isolated from other Zanthoxylum spe- cies as well as Toddalia asiatica. It is usually isolated in the form of its chloride salt, and is noted mostly for its antimalarial and cardiovascular activities [113–115]. It has also been extensively investigated for its wide variety of bioactivity including its anti-tumor activity against various malignancies. Nitidine is a very strong inhibitor of topoisomerase I en- zyme at 0.05–0.3 μM with significant selectivity. However, its effect on topoisomerase II is only moderate [116,117]. DNA topoisomerases are enzymes that regulate the conforma- tional changes in DNA topology by catalyzing the concerted cleavage and polymerization of DNA strands during cellular growth. Recent studies have identified them as putative targets for drug design against various forms of cancers. Nitidine also impedes breast Molecules 2021, 26, x FOR PEER REVIEW 15 of 50 Figure 12. Chemical structure of the quaternary ammonium salt alkaloid Sanguinarine with a summary of its biological activity towards selected cancer targets. Chelerythrine 79, isolated from Chelidonium majus, Z. xanthoxyloides, Z. clavaherculis, Molecules 2021, 26, 7134 and Z. rhoifolium among others, is a potent, selective, and cell-permeable prote1i5no kf 4in8 ase C inhibitor [105]. Chelerythrine exhibits its antitumor properties by inhibiting the prolifera- tion of androgen-independent prostate cancer cells DU145 and PC-3 at concentrations of 5 antiodn 1o0f μanMd r[o1g0e6n]-.i nWdeepsteenrdne nbtloptr oasntaatleyscaisn creervceealllesdD Uth1a4t5 7a9n dinPhCib-3itaetdc omnecetanstrtaatsiiosn osfo pf r5ostate canacnedr 1c0elµlsM by[1 s0u6]p. pWrestseirnngb MloMt aPn-a2ly, sMisMrePv-e9a,l eadndth uatP7A9 iannhdib aitlesdo mboeotasstteadsi sthoef epxropsrteastesion of endcaongceenrocuelsl sibnyhisbuiptoprse sTsiInMg PM-M1 Pan-2d, MTMIMPP-9-,2a nads uwPeAlla ansd palsaosmboionsotegdenth aecetxivparetsosri oin hofibitors (PAenI-d1o agnendo PuAs iIn-2h)i b[i1t0o6rs].T IInM vPi-t1roa nadndT IiMn Pv-i2vaos swtuedllieass phlaavsme ainlsoog ednisaccltoivsaetdo rthineh eibffietocrtss of 79 on (tPhAeI -g1raonwdthPA inI-h2)ib[1it0i6o]n. Iannvdit raopaonpdtoinsisv iivnodsutuctdiioens hoanv eHaElsKo-2d9is3c laonsedd SthWe-e8f3fe9c trsenofa7l 9cancer cellosn [1th0e7]g.r Cowhethleirnyhtihbriitnioen, 7an9d, aalpsoo pstiogsnisifiincadnutcltyio innhonibHitsE Kth-2e9 p3haonsdpShWor-y83la9tiroenna ol fc aenxcterarcellu- lar cells [107]. Chelelusilagrnsailg-rneagl-urelagtue rdy tkhrlatedin inaes,e79, akinas e(E(R lsKo) siagnndifi cAaknttERK) and Akt lyacinhiacccoomm bits papna tnhie phosphiededby buyp ruep orryelgautiloantiof extracel-gulation oofnp 5o3f, apn5d3, and dowdonwrengreugluatlaiotino noof fBBccl-l-22,, ccaassppaassee--33,,a annddP APARPR(PF i(gFuigreu1r3e) 1[130) 7[]1.07]. FigureF i1g3u.r Ce h13e.mCihceaml sictarul scttruurcetu orfe CofhCelheerlyertyhtrhinrien ewwitihth aa ssummarry ooffi tistsb bioiloolgoigcaiclalc taivctitivyittoyw taorwdsasredlse csteldecctaendce cratnarcgeert sta. rgets. NiNtiditiidnien e808 0isis ffoouunndd mmoosstltylyin inth tehreo ortosootfsZ oafn Zthaonxythluomxynliutimdu nmit(iFdaugmar a(nFiatgidaar)a, Zn.itgiidllae)ti,i Z. gil- (Fagara macrophylla), Z. tessmanii, and Z. chalybeum (Fagara chalybea). Nitidine was first letiri e(pFoargtaerdaf mroamcrZop. nhiytlidlau)m, Zin. t1e9s5sm8 bayniAi, rathnudr Zet. aclh.a[l1y0b8e]u. Imt w(Faasglaartear crheaployrbteead).f rNomitidZi.ngeil lwetiais first rep(oFratgeadra fmroamcr oZph. ynliltai)dbuymT ionr t1o95a8n dbyA Addrtaheu-Mr eent saalh. [i1n081]9.7 I0t, wWaasl llaettearl .reipno1r9t7e1d, farnodmF iZsh. gilletii (FaagnadraW maatcerrompahnylilna)1 b97y2 T[1o0r9to–1 a1n2d]. SAindcdeateh-eMn,eint shaahs binee 1n9i7s0o,l aWteadlflr eotm alo. tihne r19Z7a1n,t haonxdyl Fumish and Wastpeercmiesaans iwne 1ll9a7s2T [o1d0da9l–ia1a1s2ia].t iScai.nIctei sthuseuna, lilyt hisaosla btedenin itshoelafoterdm forfoimts cohtlhoerird Ze asanltth, oaxnydluism spe- ciesn aoste wd emllo satsl yTfoodrdiatslia natsiimatailcaar.i aItl aisn duscuaradlliyov iassoclualtaerda icnti vthiteie sfo[r1m13 –o1f1 5it]s. Icthhlaosriadlseo sbaelet,n and is noteexdte mnsoivsetllyy ifnovre sittisg aatnetdimfoarliatrsiwali daenvda criaertdy ioofvbaioscauctliavrit yacinticvluitdieins g[1it1s3a–n1t1i-5tu].m Ito rhaacst iavlistyo been extaegnasiinvsetlvya irniovuessmtigalaigtendan fcoire si.tsN witiiddien eviasraievteyr yofs tbrioonagcitnivhiitbyit oinrcolfutdopinogis oitms earnatsie-tIuemnzoyrm aectivity agaaitn0s.t0 5v–a0r.3ioµuMs mwiatlhigsnigannificiceasn. tNseilteicdtiinviet yi.sH ao wveervye rs, tirtsonefgfe cint honibtiotopro iosof mtoepraosiesoIImiseornaslye I en- moderate [116,117]. DNA topoisomerases are enzymes that regulate the conformational zymchea nagt e0s.0in5D–0N.3A μtoMpo wloigtyhb syigcantiafliyczainntg stehleeccotnivcietryte. dHcolewaveavgeera, nitds peoflfyemcte orinza ttoiopnooifsoDmNeArase II is osntrlayn mdsodduerriantge c[1e1ll6u,l1a1r7g]r.o DwNthA. Rtoepceonitsostmudeireassehsa vaerei deennztyifimedest hthemat aresgpuultaatteiv tehtea crgoentfsorma- tionfoarl dcrhuagndgesi gin DagNaiAns ttovpaoriloougsyf obrym csaotaf lcyaznicnegrs t.hNei tciodninceeartlseodi cmlepaevdaegs eb raenadst pcaonlycemr ceerlilzation of DmNigAra tsiotrnaanndds idnvuarsiinogn cveialliunlaacrt igvraotiwontho.f Rc-eScrce/nFtA sKtupdaitehsw haayvaes iwdelnl taisfideodw tnhreemgu alast ipountative targofetMs MfoPr- 2darnudg MdMesPig-9n[ 1a1g8a].inAsnt ivnavriivoousst ufodrymresv oeaf lecdanthceerssu. pNprietisdsiionne oaflhsoep iamtopceeldluelsa rbreast carcinoma cell proliferation by the inhibition of the JAK1/STAT3 signaling pathways. Associated with this is the increased levels of p21 and Bax as well as decreased levels of cyclinD1, CDK4 and Bcl-2 (Figure 14) [119]. The existence of nitidine and other benzophenanthridine alkaloids as quaternary salts is a major problem in their study for cancer chemotherapy and other diseases, especially in vivo studies, because of their poor absorption and hence bioavailability. In attempts to find possible drug delivery systems to enhance their cancer chemotherapeutic profiles, the pharmacodynamics of nitidine chloride on various types of nanoparticles have been studied and found to reduce toxicity and enhance anticancer effects [120]. Closely related to nitidine but less toxic are fagaronine, 81 and fagaridine, 82, which are major constituent alkaloids of Z. xanthoxyloides (Fagara xanthoxyloides). The two com- pounds have been extensively investigated for their mutagenic activities [121,122]. The anticancer activity of fagaronine was first reported by Messmer and his coworkers, who Molecules 2021, 26, 7134 16 of 48 Molecules 2021, 26, x FOR PEER REVIEW f ound it to effect complete cure in mice infected with the P-388 lymphocytic leukemia [123]1.6 of 50 It was subsequently found to be very active against chronic myeloid leukemia (cell line K 562) as well as several other cancers of viral origin [124]. Fagaronine exhibits its an- canticleeur kceemll imc iagcrtiavtiitoynb aynidnh iinbvitainsigobno vthiaT ionpaocitsiovmateiorans eofI ca-nSdrcII/FaAt cKo npcaetnhtwraatiyo nass owf e3l0l aans ddown- 25 µM [125]. Fagaridine, first reported from Z. xanthoxyloides by Torto et al., [126] inhibits regtuoplaotiisoonm eorfa sMe MI, ePf-fe2c tainvedl yMstMabPil-iz9e s[1t1o8p]o. isAonm einra sveivI-oD NstAudbyin areryvecaolmedpl etxh,ea nsudpinptreercsasi-on of heplaatteoscienltlouDlaNr cAar[c1i2n7o].mAa scyenltlh pertoicliifseormateironof bfyag tahreid iinnhei,bNit-i1o0n9 ,oifs tshaeid JAtoKb1e/SmToAreTs3t asbiglenaling patahnwd apyosss. eAssssgorecaiatetreadc twiviitthy tthaisn iasl lththee inactrueraaslleydo lcecvuerrlisn ogfb pe2n1zo apnhde nBaanxth arsid wineella laksa ldoeidcsreased lev(eFlisg uorfe c1y5c)li[n10D91]., CDK4 and Bcl-2 (Figure 14) [119]. Molecules 2021, 26, x FOR PEER REVIEW 17 o f 50 FigurFei g1u4r.e C1h4e. mChiceaml isctarlusctrtucrteu roef oNf iNtiidtiidnien eanandd aa ssuummary ooffi titssb bioiololgoigciaclaalc aticvtiitvyitoyw toarwdasrsdelse csteeldecctaendc ecratnacregre ttsa.rgets. The exOisHtence of nitidine and other benzophenanthOrHidine alkaloids as quaternary salts is a major problem in their study for cancer chemotherapyO and other diseases, espe- cially in vivOo studies, because of their poor abNso +rption and hence bioavailability. In at- te+mpts to find possible drug deliveOry systems to enhance their cancer chemotherapeutic N O profiles, the pharmacodynamics of nitidine chloride on various types of nanoparticles O have been studied and found to redOuce toxicity and enhance anticancer effects [120]. Closely related to nitidine but less toxic are fagaronine, 81 and fagaridine, 82, which Fagaronine,a8r1e major constituent alkaloids of Z. xanthoxyloides (Fagara xanthoxyloides). The two com-pounds have been extensively invesFtiaggaaterdid fionre t,h8e2ir mutagenic activities [121,122]. The Cancer: Leukemia anticancer activity of fagaronine wCasa nficrestr :reLpeourkteedm biay Messmer and his coworkers, who Cancer Cell: P388 found it to effect complete cure in mice infected with the P-388 lymphocytic leukemia [123]. It was subsequently found toC baen vceerryC aecltli:vPe 3a8g8ainst chronic myeloid leukemia (cell Biological Target: Tlionpeo Kis o5m62e) raass ewIell as several otheBr icoalnocgeircsa loTf avrirgael to: rTigoipno [i1s2o4m]. eFragsaerIonainnde IeIxhibits its IC50: 30 μM antileukemic activity by inhibitingI Cbot:h2 T5oμpMoisomerase I and II at concentrations of 30 and 25 μM [125]. Fagaridine, first re5p0orted from Z. xanthoxyloides by Torto et al., [126] Figure 15. Chemical struicntuhriebs iotfs F taogpaoroinsionme aenrda sFea gIa, reidffineec twivitehl ya ssutmabmilairzye osf tohepiro bisiolmogeicraal saec tIiv-DityN toAw abridnsa sreyle ctoemd plex, and cancer ttargetts.. intercalates into DNA [127]. A synthetic isomer of fagaridine, N-109, is said to be more stable and possess greater activity than all the naturally occurring benzophenanthridine alk22a..22lo.. iSd--Bs aa(ssFeeiddg Hueretteee rr1oo5ccy)y cc[ll1ees0s 9 ]. IIn aaddddiittiioonn toto ththe eNN- a-nadn Od-O b-asbeads ehdethereotecyroccleysc,l mese,dmiceidnaicli cnhaelmchisetms hisatvseh sahvifetesdh itfhteidr athtteeinrtaiottne ntoti oSn-btaoseSd-b haesetedrohceytecrleosc ybcelceasubsec oafu tsheeoirf timhepirreimsspivre sbsiiovleogbiicoalol gaitctrailbautttersib aust easntais- caannticcearn, caenrt,idaniatbideitaicb, eatnict,ifaunntgifauln agnadl andtihaynptiehrtyepnesritveen asigveentasg [e1n2t8s].[ 1C2u8]r.reCnutlryr,e snotmly,e sFoDmAe aFpDpAroavpepdr dorvuegds dhrauvges Sh-haevteerSo-chyectleerso acys cloerse ams ocioerteiems foire tihees tfroerattmh entrte oaft mvaerniotuosf dviasreiaosues idnicsleuadseinsgin calundceinr g[1c2a8n]c.e Bre[l1o2w8] .aBre lsoowmaer eSs-coomnetaSin-cionngt ahientienrgochyecteleros cwycitlhes mwuitlhtitmarugletitt aarngteit- caannticcearn pcreorpperrotpieesr.t ies. Gliotoxin, 83 is a member of the epipolythiodioxopiperazine class of mycotoxins pro- duced by Aspergillus fumigatus, Eurotium chevalieri, Gliocladium fimbriatum, and most Trichoderma, and Penicillium species as well as Neosartorya pseudofischeri [129]. It belongs to the 2,5-diketopiperazine class of natural products. Compound 83 has immunosuppressive properties such as the blockage of NF-KB activation [130] and modulates the immune re- sponse, affects circulating neutrophils, suppresses reactive oxygen species (ROS) produc- tion and inhibits phagocytosis of conidia [129]. It inhibits proliferation and induces apop- tosis on colorectal and cervical cancer cells via caspase activation followed by up- and downregulations of Bax and Bcl-2, respectively (Figure 16) [131,132]. OH O OH H N SNS O Gliotoxin, 83 Cancer: Cervical Cancer Cell: SW1353, HeLa Biological Target: Bcl-2, Bax, caspase-3, 8, and 9 IC50 = 90 μM Figure 16. Chemical structure of Gliotoxin and summary of its biological activity towards selected cancer targets. During investigations aimed at repurposing Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) COX-2 selective inhibitors against MCF-7 (human breast carcinoma), HT-29 Molecules 2021, 26, x FOR PEER REVIEW 17 of 50 OH OH O O N + N+ O O O O Fagaronine, 81 Fagaridine, 82 Cancer: Leukemia Cancer: Leukemia Cancer Cell: P388 Cancer Cell: P388 Biological Target: Topoisomerase I Biological Target: Topoisomerase I and II IC50: 30 μM IC50: 25 μM Figure 15. Chemical structures of Fagaronine and Fagaridine with a summary of their biological activity towards selected cancer targets. 2.2. S-Based Heterocycles In addition to the N- and O- based heterocycles, medicinal chemists have shifted their attention to S-based heterocycles because of their impressive biological attributes as anti- cancer, antidiabetic, antifungal and antihypertensive agents [128]. Currently, some FDA Molecules 2021, 26, 7134 approved drugs have S-heterocycles as core moieties for the treatment of variou17so df i4s8eases including cancer [128]. Below are some S-containing heterocycles with multitarget anti- cancer properties. Gliotoxin, 83 is a member of the epipolythiodioxopiperazine class of mycotoxins pro- duceGdl iobtyo xAins,p8e3rgiislluasm fuemmbigeartuosf, thEeureoptiiupmol ycthheiovdaliioerxio, pGiplieorcalzadiniuemcl afsims borfiamtuymco, toaxnidn smost pTrroidchuocdeedrmbya, Aanspde rPgeilnluicsilfluiummig saptuesc,ieEsu arost wiuemllc ahse vNaleioesrai,rtGolriyoacl padseiuumdofifimscbhreirait u[1m2,9a].n Idt bmeloosnt gs to Ttrhiceh 2od,5e-rdmiak,eatnodpiPpeenriacizlilinuem clsapsesc oiefs naastuwrealll pasroNdeuoscatrst.o Cryoamppseouudonfids c8h3e rhia[s1 2im9].mItubneolsounpgsprtoessive tphe 2,5-diketopiperazine class of natural products. Compound 83 has immunosuppressiveprrooppeertriteiesss usuchcha asst htheeb blolockckaaggeeo of fN NFF- -KBBa accκ titvivaatitoionn[ 1[3103]0]a nanddm mododulualtaetsesth teheim immmunuene re- rsepspoonnsese, ,afaffefecctsts ccirirccuulalattiinngg nneeuuttrroopphhiillss,, ssuupppprreesssseess rreeaaccttiivvee ooxxyyggeenn ssppeecciieess( (RROOSS))p prroo-duc- dtuiocnti oannda nindhiinbhitisb iptshapghoacgyotcoystioss oisf ocfoncoidniiad i[a12[192].9 I]t. iInt hinibhiitbsi tpsrporliofleifreartaiotino nanadn dinidnudcuecse sapop- atpoospist oosnis coonlocorelocrteaclt aalnadn dcecrevrivciacal lccaanncceerr cceellllss vviaiac acsapsapsaesaec aticvtaivtiaotniofonl lfoowlleodwbeydu bpy- aunpd- and ddoowwnnreregguulaltaitoinosnos foBf aBxaaxn adnBdc Bl-c2l,-r2e,s rpeescptievcetilyve(lFyig (uFrigeu1r6e) [1163)1 [,113321],.132]. OH O OH H N SN S O Gliotoxin, 83 Cancer: Cervical Cancer Cell: SW1353, HeLa Biological Target: Bcl-2, Bax, caspase-3, 8, and 9 IC50 = 90 μM FFigiguurere1 61.6C. Chehmemiciaclaslt rsutrcutuctrueroef oGfl iGoltiooxtionxain dansudm summarmyaorfyi tosfb iitosl obgioiclaolgaiccatilv aitcytitvoiwtya rtodws saerldecst esedlected ccaanncceerrt atragregtest.s. DDuurirninggin invevsetsigtiagtaiotinosnasi maiemdeadt aret prueprpuorspionsginNgo nNsotenrsotiedraoliAdanlt iA-Inntfli-aImnfmlaamtomryaDtorruyg Ds rugs ((NNSSAAIDIDs)s)C COOXX-2-2s esleelceticvtievien hinibhiitboirtsorasg aaignasitnMst CMF-C7F(-h7u m(haunmbarne absrtecaasrtc icnaormcina)o,mHaT)-,2 H9 T-29 (human colorectal adenocarcinoma), and A549 (human lung carcinoma) cancer cell lines, two diphenyl thiazole derivatives 84 and 85 were found to exhibit the highest potency with IC50 in the micromolar range [133]. Despite the weak activity of the two compounds against tubulin polymerization assays, they showed remarkable inhibition of EGFR and BRAF with IC50 ≤ 40 µM [133]. In the search for naturally occurring compounds with multitargeting potential against breast cancer cell lines, the alkaloid ellipticine 86 was found to exhibit topoisomerase I and tubulin polymerase inhibition [134]. However, it was found to have numerous deleterious side effects. The continued search for other heterocyclic compounds with activities like that of ellipticine but with reduced deleterious side effects led to the investigation of several heterocyclic compounds containing both nitrogen and sulfur. Six benzothienoquinazoli- none derivatives were synthesized via isosteric iteration. Two of the six, compounds 87 and 88, were the most active compounds inhibiting topoisomerase 1 and tubulin polymer- ization [135]. The two compounds also exhibited aggressive activity against MDA-MB-231 cell lines with IC50 of 3.88 µM and 4.69 µM, respectively and moderate inhibition activity against MCF-7 cells at 40.70 and 41. 99 µM (Figure 17) [135]. The ability of a bioactive compound to quench activities that lead to abnormal cell growth has been applied in the treatment of inflammatory-related diseases. Five highly reactive naphthoquinones (89–93) investigated by Aly et al. showed promising anti-tumor activity via cell cycle arrest in the pre-G1 and G2/M phases and downregulation of cyclin- dependent kinases (CDK) [136]. Three of them, 91–93 were found to be strong inhibitors of cyclic dependent kinases with 91 being the most potent. Compound 91 attenuated eight isoforms of CDK and phosphor-tyr15 and also induced apoptosis and cell cycle arrest by downregulating pre-G1 and G2/M phases, respectively [136]. In similar studies involving heterocyclic compounds containing nitrogen and sulphur, ten [1,2,4]-triazine derivatives 94–103 (Table 1) were investigated for their anti-cancer properties. The compounds were synthesized from phenylisothiocyanate and ethanol- Molecules 2021, 26, x FOR PEER REVIEW 18 of 50 (human colorectal adenocarcinoma), and A549 (human lung carcinoma) cancer cell lines, two diphenyl thiazole derivatives 84 and 85 were found to exhibit the highest potency with IC50 in the micromolar range [133]. Despite the weak activity of the two compounds against tubulin polymerization assays, they showed remarkable inhibition of EGFR and BRAF with IC50 ≤ 40 μM [133]. In the search for naturally occurring compounds with multitargeting potential against breast cancer cell lines, the alkaloid ellipticine 86 was found to exhibit topoisomer- ase I and tubulin polymerase inhibition [134]. However, it was found to have numerous deleterious side effects. The continued search for other heterocyclic compounds with ac- tivities like that of ellipticine but with reduced deleterious side effects led to the investi- gation of several heterocyclic compounds containing both nitrogen and sulfur. Six ben- zothienoquinazolinone derivatives were synthesized via isosteric iteration. Two of the six, compounds 87 and 88, were the most active compounds inhibiting topoisomerase 1 and tubulin polymerization [135]. The two compounds also exhibited aggressive activity against MDA-MB-231 cell lines with IC50 of 3.88 μM and 4.69 μM, respectively and mod- Molecules 2021, 26, 7134 erate inhibition activity against MCF-7 cells at 40.70 and 41. 99 μM (Figure 17) [135]1.8 of 48 The ability of a bioactive compound to quench activities that lead to abnormal cell growth has been applied in the treatment of inflammatory-related diseases. Five highly reactive naphthoquinones (89–93) investigated by Aly et al. showed promising anti-tumor accotnivtaitiyn ivniga ctreilel tchyycllaem arinreesvt iina tahme purleti--Gco1m anpdo nGe2n/tMre pahctaisoens. aTnhde dsoywnnthreegsiuzleadtioconm ofp coyucnlidns- dweepreenfdouenntd ktionabseeps o(tCeDntKa)t [n1a3n6]o.m Tohlraere aonfd thseumb-,m 9i1c–r9o3c wonecreen ftoruatnidon tso tboew satrrdosngsi xinthyirboistionres okfi ncayscelicre dceeppetonrdse(nct- Mkienta,sce-sK wit,itFhl t9-31, bVeEinGgF tRhe-2 m, EoGstF pRo,taenndt. PCDomGFpRou).nCdo 9m1 paottuenndua9t5edb oeuignhdt isstorofonrgmlys toof aClDl tKh eanredc epphtoosrpsheoxrc-etyprt1E5G aFnRd [a1ls3o7 ]i.nEdsutcimeda taipoonpotof sthise asnedri ceeslel fcfiyccalec yarargeastin bsyt dPoIMw-n1reagctuivlaittiynsgh porwe-eGd1c oanmdp Gou2n/Mds p9h5a–s9e9s,a rnedsp1e0c1t–iv10e3lya [s1t3h6e].m ost potent [137]. Molecules 2021, 26, x FOR PEER REVIEW 19 of 50 In similar studies involving heterocyclic compounds containing nitrogen and sul- phur, ten [1,2,4]-triazine derivatives 94–103 (Table 1) were investigated for their anti-can- cer properties. The compounds were synthesized from phenylisothiocyanate and ethanol- containing triethylamine via a multi-component reaction. The synthesized compounds were found to be potent at nanomolar and sub-micro concentrations towards six tyro sine Figure 17. SStrtruucctutureress oof fthteh edidkpiihpnehanesynely trlheitcahezipaoztleooslr es8s 4( 8ca4-nMdan e8dt5,, 8ce5-lKl,ipeitlt,li icFpinlttiec- 3i8n,6 eV, b8Ee6Gn, zbFoeRtnh-z2ioe, ntEhoGiqeunFioRnq,a uzaionnldainz PonDlienGso 8Fn7Re sa)n.8 dC7 o8a8mn wdpi8oth8u awn dsiut h9m5a- bound smuamrym oafr ythoefirt hbeioirlobgioiclaolg aiccatilvaictsyttir vtooitnwygatlorydw sta osr edalsellcs tetelhdeec c taerednccceearpn ttcaoerrrgste atesrxg. ceetsp.t EGFR [137]. Estimation of the series efficacy against PIM-1 activity showed compounds 95–99 and 101–103 as the most potent [137]. TabTlaeb1le. I1n.h Iinbhitiobrityorayc taivcittiyviotyf pofr optreointekinin kaisneaesne zeynmzyems (eIsC (5I0C/n/MnM) b) ybysy snytnhtehseizsiezded1, 21,,42-,4tr-itarziainziende edreivriavtiavtievs50 e[s1 3[173].7]. CCoommppoouunndd NNoo.. CpdC pdc-Met c-Mce-tKit c-FKlitt-3 VFEltG-3FR-2 VEGEFGR-F2R EGFRPDGFPRD GFR PPiimm--11 94 94 3.42 3.420.32 0.03.224 0.204.63 0.630.42 0.42 0.57 0.57 >10,,000 95 0.24 0.23 0.19 0.59 1.03 0.36 420 96 0.35 3.08 3.16 5.73 2.92 2.73 260 97 0.27 0.68 0.47 0.83 5.06 2.27 230 98 0.32 0.36 0.29 0.64 0.52 0.38 400 99 0.48 1.17 1.34 0.93 2.53 1.03 >10,000 MMoolleeccuulleess 22002211,, 2266,, xx FFOORR PPEEEERR RREEVVIIEEWW 1199 ooff 5500 IInn ssiimmiillaarr ssttuuddiieess iinnvvoollvviinngg hheetteerrooccyycclliicc ccoommppoouunnddss ccoonnttaaiinniinngg nniittrrooggeenn aanndd ssuull-- pphhuurr,, tteenn [[11,,22,,44]]--ttrriiaazziinnee ddeerriivvaattiivveess 9944––110033 ((TTaabbllee 11)) wweerree iinnvveessttiiggaatteedd ffoorr tthheeiirr aannttii--ccaann-- cceerr pprrooppeerrttiieess.. TThhee ccoommppoouunnddss wweerree ssyynntthheessiizzeedd ffrroomm pphheennyylliissootthhiiooccyyaannaattee aanndd eetthhaannooll-- ccoonnttaaiinniinngg ttrriieetthhyyllaammiinnee vviiaa aa mmuullttii--ccoommppoonneenntt rreeaaccttiioonn.. TThhee ssyynntthheessiizzeedd ccoommppoouunnddss wweerree ffoouunndd ttoo bbee ppootteenntt aatt nnaannoommoollaarr aanndd ssuubb--mmiiccrroo ccoonncceennttrraattiioonnss ttoowwaarrddss ssiixx ttyyrroossiinnee kkiinnaassee rreecceeppttoorrss ((cc--Meett,, cc--KKiitt,, FFlltt--33,, VVEEGGFFRR--22,, EEGGFFRR,, aanndd PPDDGGFFRR)).. CCoommppoouunndd 9955 bboouunndd ssttrroonnggllyy ttoo aallll tthhee rreecceeppttoorrss eexxcceepptt EEGGFFRR [[113377]].. EEssttiimmaattiioonn ooff tthhee sseerriieess eeffffiiccaaccyy aaggaaiinnsstt PPIIM--11 aaccttiivviittyy sshhoowweedd ccoommppoouunnddss 9955––9999 aanndd 110011––110033 aass tthhee mmoosstt ppootteenntt [[113377]].. TTaabbllee 11.. IInnhhiibbiittoorryy aaccttiivviittyy ooff pprrootteeiinn kkiinnaassee eennzzyymmeess ((IICC5500//nnMM)) bbyy ssyynntthheessiizzeedd 11,,22,,44--ttrriiaazziinnee ddeerriivvaattiivveess [[113377]].. CCoommppoouunndd NNoo.. CCppdd cc--MMeett cc--KKiitt FFlltt--33 VVEEGGFFRR--22 EEGGFFRR PPDDGGFFRR PPiimm--11 Molecules 2021, 26, 7134 19 of 48 9944 33..4422 00..3322 00..2244 00..6633 00..4422 00..5577 >>1100,,000000 Table 1. Cont. Compound No. Cpd c-Met c-Kit Flt-3 VEGFR-2 EGFR PDGFR Pim-1 9955 95 00..2244 0.2400..2233 0.020.3.1199 0.1009..5599 0.5911..0033 1.03 00..3366 0.36 442200 9966 96 00..3355 0.3533..0088 3.303.8.1166 3.1556..7733 5.7322..9922 2.92 22..7733 2.73 226600 9977 97 00..2277 0.2700..6688 0.060.8.4477 0.4007..8833 0.8355..0066 5.06 22..2277 2.27 223300 9988 98 00..3322 0.3200..3366 0.030.6.2299 0.2009..6644 0.6400..5522 0.52 00..3388 0.38 440000 9999 99 00..4488 0.4811..1177 1.11.7.3344 1.3004..9933 0.9322..5533 2.53 11..0033 1.03 >>1100,,,000000 Molecules 2021, 26, x FOR PEER REVIEW 20 of 50 100 100 0.42 0.420.62 0.062.49 0.409.26 0.260.38 0.38 0.41 0.41 360 101 101 0.68 0.680.52 0.052.21 0.201.53 0.530.80 0.80 0.46 0.46 102 102 290 0.49 0.490.16 0.016.24 0.204.37 0.370.49 0.49 0.22 0.22 103 103 0.42 0.42 0.63 0.51 1.08 >10, ,000 0.63 0.51 1.08 0.74 0.74 0.80 0.80 2.3. O-Heterocyclic 2.3. O-HSeevteerroacly scylinc thetic and naturally occurring oxygen heterocycles belonging to various comSepvoeurnadl scylnasthsest iscuacnhd ans atteurpraelnlyoiodcsc,u croruinmgaorxinysg, efnlahveotneoriodcsy calneds baecleotongeingintso hvaavreio buesen coimnvpeosutingdatcelda sfsoers tshuecihr asntie-rcpaenncoerid asc,tciovuitmiesa.r iTnhsr, eflea vnoenwo indastuanradllayc eotcocguernrings haacveteobgeennins from the family Annonaceae, isolated from the seeds of Annona squamosa (compounds 104– 106, (Figure 18) have been reported by Pardhasaradhi et al. to possess radical-generating properties against MCF-7 and K-562 [138]. Studies by other researchers revealed that the compounds also induce apoptosis accompanied by organelle deformations like DNA frag- mentation and phosphatidyl serine externalization [139]. In the area of cancer chemotherapy, transcriptional factors in modulation target have received little attention. In this regard, Youn et al. investigated the regulation of atypical oncogenes, particularly NF-κB and STAT3 transcriptional factors. They found that the ses- quiterpene lactones, 107–111 (Figure 18) isolated from Vernonia cinerea exhibited promis- ing TNF-α-induced NF-κB and NO activity [140,141]. While compound 109 was the most potent with IC50 value of 0.6 μM against TNF-α-induced NF-κB and 2.0 μM against NO targets, the other compounds showed moderate inhibition with IC50 values between 10.2 and 13.6 μM [141]. Furthermore, all the sesquiterpene lactone isolates exhibited significant STAT3 aberrations [140]. Similarly, compound 112 was screened against human umbilical vein endothelial cells (HUVECs). It significantly suppressed the vascular endothelial growth factor and downstream hypoxia-inducible factor-1α (HIF-1α), which are used by tumor cells to survive and grow in microenvironments, at a very low concentration of 0.026 μM [142]. Ethnobotanical and phytochemical studies of Eclipta prostrata led to the isolation of four compounds 113–117 (Figure 18) [143]. Mechanistic studies revealed that 101 activated caspase dependent apoptosis via tight inhibition of 5-LOX at 2.5 μM [143,144]. Compound 114, which differs from 115 by an additional glycone at the C-28 position, induces apop- tosis in a caspase-independent manner via blocking of significant pathways like mamma- lian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) in human ovarian cancer cells at 94.87 μM [145]. The anticancer property of luteolin, 116, a tetrahy- droflavone, was associated with induction of apoptosis via redox regulation, DNA dam- age, and protein kinases in inhibiting proliferation of cancer cells [146]. Compound 116 also suppresses metastasis and angiogenesis through downregulation of survival path- ways, such as PI3K/Akt, NF-κB, and MAPK [146]. A 7-O-glucoside derivative of 116 was found to decrease the proliferation of HepG2 cells along with changes in nuclear structure and DNA fragmentation in a dose dependent manner [147]. The effect of 116 on growth Molecules 2021, 26, 7134 20 of 48 investigated for their anti-cancer activities. Three new naturally occurring acetogenins from the family Annonaceae, isolated from the seeds of Annona squamosa (compounds 104–106, (Figure 18) have been reported by Pardhasaradhi et al. to possess radical-generating Molecules 2021, 26, x FOR PEER REVIEpWro perties against MCF-7 and K-562 [138]. Studies by other researchers reveale2d2 othf 5a0t the compounds also induce apoptosis accompanied by organelle deformations like DNA fragmentation and phosphatidyl serine externalization [139]. O O O O OH OH OH * * O HO O * * 8 7 * O * O 11 3O * O 3 O 7 OH OH 9 HO OH 104 105 O 106 HO O OH R3O O O O HO O O O O O O O O HO O O OH HO O R2O A = Tiglogyl O OR B = 2 -Methyacryloyl O O O 1 HO O 107 R1 = A, R2 = H, R3 = H, 108 112 113 R1 = Acetyl, R2 = A, R3 = H, 109 R1 = Acetyl, R2 = B, R3 = H, 110 R1 = Acetyl, R2 = A, R3 = CH3, 111 H OH 28 OH OH O 28 HO OH OH O O OO HO OH OH HO H H OH O O O OHHO O H H OH OHO HO OH HO O O OH OH OH 114 115 OH 116 OH HO O O O O OH HO H HO OH H H O HO OH O O O OH OH O HCH3 O O O 114 118 H HOphiobolin A, 120 119 OH OH O OHH HH O O HO O HH O H 121 Phorbaketal A, 123 FFiigguurree 1188.. SSttrruuccttuurreess ooff aacceettooggeenniinnss1 10044––110066, ,s seesqsquuitietreprpeneneela lcatcotnoense,s1, 0170–71–1111a1n adncdo cmopmopuonudnsdisso ilsaotleadtefdro fmroEmcl iEpctlaipptrao sptrroasta- t1r1a3ta– 111173.–117. In the area of cancer chemotherapy, transcriptional factors in modulation target have received little attention. In this regard, Youn et al. investigated the regulation of atypical oncogenes, particularly NF-κB and STAT3 transcriptional factors. They found that the sesquiterpene lactones, 107–111 (Figure 18) isolated from Vernonia cinerea exhibited promis- ing TNF-α-induced NF-κB and NO activity [140,141]. While compound 109 was the most potent with IC50 value of 0.6 µM against TNF-α-induced NF-κB and 2.0 µM against NO targets, the other compounds showed moderate inhibition with IC50 values between 10.2 and 13.6 µM [141]. Furthermore, all the sesquiterpene lactone isolates exhibited significant STAT3 aberrations [140]. Similarly, compound 112 was screened against human umbili- cal vein endothelial cells (HUVECs). It significantly suppressed the vascular endothelial growth factor and downstream hypoxia-inducible factor-1α (HIF-1α), which are used by tumor cells to survive and grow in microenvironments, at a very low concentration of 0.026 µM [142]. Figure 19. Structure of the triterpenoid glycoside Glycyrrhizic acid with a summary of its biological activity towards selected cancer targets. Molecules 2021, 26, 7134 21 of 48 Ethnobotanical and phytochemical studies of Eclipta prostrata led to the isolation of four compounds 113–117 (Figure 18) [143]. Mechanistic studies revealed that 101 ac- tivated caspase dependent apoptosis via tight inhibition of 5-LOX at 2.5 µM [143,144]. Compound 114, which differs from 115 by an additional glycone at the C-28 position, in- duces apoptosis in a caspase-independent manner via blocking of significant pathways like mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) in human ovarian cancer cells at 94.87 µM [145]. The anticancer property of luteolin, 116, a tetrahydroflavone, was associated with induction of apoptosis via redox regulation, DNA damage, and protein kinases in inhibiting proliferation of cancer cells [146]. Compound 116 also suppresses metastasis and angiogenesis through downregulation of survival path- ways, such as PI3K/Akt, NF-κB, and MAPK [146]. A 7-O-glucoside derivative of 116 was found to decrease the proliferation of HepG2 cells along with changes in nuclear structure and DNA fragmentation in a dose dependent manner [147]. The effect of 116 on growth inhibition factors was attributed to the G2/M phase arrest and ROS generation with high phosphorylation of c-Jun N-terminal kinases (JNK) [147]. Another multitarget anticancer compound with high selectivity for cell cycle regulatory proteins is the isoflavone 118 [148]. Collectively, compound 118 disrupts activities of cyclin dependent kinases and other cell cycle regulatory proteins resulting in cell cycle arrest with IC50 values within the micro- molar range [148]. Similarly, compound 119, a fungal metabolite with potent antitumor and anti-inflammatory effects with efficacy at 10 µM against prostate cancer cell lines was observed to inhibit both STAT3 and NF-κB transcription and destabilize microtubules and G2/M cell cycle arrest [149,150]. Though the exact mechanism of action of compound 120 is not known, it is reported to have effects on proliferation and migration of human cancer cells. Bury et al. found that 1 µM of compound 120 induced changes in the organization of the actin filaments in the cytoskeleton and disruption of Ca2+-activated K+ channel activity [151]. The marine environment has been a productive source of potential anticancer agents. One of the most recognized genera as a rich source of eunicellin-based diterpenoids, such as the pachycladins, is Cladiella sp. [152]. One such isolate, compound 121 inhibited breast cancer cell growth via down-regulation of the NF-κB and up-regulation of the Heme oxygenase-1 (HO-1) pathways in a dose-responsive manner, with an IC50 value of 1.6 µM [152]. Pharmacophoric group analysis indicated that the acetate and butyrate moieties at C-3 and C-11 were responsible for optimal antiproliferative activity [152]. Phorbaketal A, a tricyclic sesterterpenoid phorbaketal, 122 isolated from the marine sponge Phorbas sp by Yun-Ji Seo was also evaluated for its anticancer potential [153]. It showed significant inhibition of Lipopolysaccharide (LPS)-induced production of nitric oxide (NO) via dampening of inducible nitric oxide synthase (iNOS). It further showed ex- pression at the transcriptional level along with NF-κB deactivation in RAW 264.7 cell [153]. Compound 122 also induced ROS generation through HO-1 expression at 10 µM [153,154]. Glycyrrhiza uralensis Fisch (Glycyrrhiza glabra Linn), also known as licorice or Chinese liquorice is one of the most important and oldest phytomedicines in China [155–157]. It has been used for ages for the treatment of several diseases, especially those of inflammatory origins. It is also approved as a food additive and various medicinal preparations as a sweetener. Recent attention on the crude drug as well as its chemical components has been on its anticancer properties. It acts by modulating pro-inflammatory mediators and activat- ing the immune system [158,159]. In vitro studies on Glycyrrhizic acid (Glycyrrhizin), 123, a triterpenoid glycoside from the roots of the plant, showed that the compound downregu- lates pro-inflammatory modulators NF-κB and thromboxane synthase causing apoptosis on lung adenocarcinoma, hepatoma, leukemia, stomach, and prostate cancer cell lines (Figure 19) [160–162]. Its effects on tumor growth and endometrial cancer progression are through suppression of COX-2, TNF-α, IL-1, ornithine decarboxylase (ODC) activity, DNA synthesis, and TxA2 [162–164]. The compound also downregulates reactive oxygen species (ROS)-induced damage. Molecules 2021, 26, x FOR PEER REVIEW 22 of 50 O O O O OH OH OH * * O HO O * * O 87 * * 11 3O O * O 3 O 7 9 HO OH 104 OH OH105 O 106 HO O OH R3O O O O HO O O O O OO O HO O O O OH HO O R2O A = Tiglogyl O OR B = 2 -Methyacryloyl O O O 1 HO O 107 R1 = A, R2 = H, R3 = H, 108 112 113 R1 = Acetyl, R2 = A, R3 = H, 109 R1 = Acetyl, R2 = B, R3 = H, 110 R1 = Acetyl, R2 = A, R3 = CH3, 111 H OH 28 OH OH O 28 HO OH OH O O OO HO OH OH HO H H OH O O O OHO HO OOH HO H H HO OH HO O O OH OH OH 114 115 OH 116 OH HO O O O O OH HO H HO OH H H O HO OH O O O OH OH O HCH3 O O O 114 118 H HOphiobolin A, 120 119 OH OH O OH HH H O O HO O H OH H 121 Phorbaketal A, 123 Molecules 2021, 26, 7134 22 of 4 8 Figure 18. Structures of acetogenins 104–106, sesquiterpene lactones, 107–111 and compounds isolated from Eclipta pros- trata 113–117. FFigiguurere1 91.9S. tSrturcutuctrueroef othf ethteri terirtpeernpoeindogidly gcolysicdoesiGdley Gcylryrchyizrirchaizcicd awcitdh wa istuhm am suamrymofairtys boifo iltosg bicioalogical aactcitviivtiytyto twowaradrsdsse lseeclteecdtecda nccaenrctearr gtaertsg.ets. A dihydroxyflovanone compound, Liquiritigenin, 124, isolated from the roots of the same plant [165] is an estrogenic that acts as a selective agonist of the ERβ subtype of the estrogen receptor (ER) (Figure 20) [166]. It is also reported to act as an estrogen receptor Molecules 2021, 26, x FOR PEER REVaIElpWh a (ERα) partial agonist [167]. Liquiritigenin, has been screened against hepatic cance2r3 of 50 cell SMMC-7721 and HeLa cells and found to activate apoptosis via MMP-2 activity and dephosphorylation of Akt [156,168]. FFigiguurere2 200. . SSttrruuccttuurreeo offt thheed dihihyyddroroxxyyflfolovvananonoeneL Liqiuqiurirtigtiegneininw withitha asu smummarayryof oift sitbs iboliogloicgaicl al ac- atcitviivtiyty totowwaarrddss sseelleecctted cancer ttarrggeettss.. IsIsooaanngguustsotonneeA A, ,1 12255i sisa a 66--pprreennyylalateteddi sisooflfalavvaannoonneel ilpipididm moolelceuculelei siosolaltaetdedf rforomm the trhoeorto ooft GoflyGcylyrcryhrirzhai z(aFi(gFuigrue r2e12).1 )C. oCmopmopuonudn d12152 5inidnudcuecse sapaoppoptotosissi sinin SSWW448800 hhuummaann colo- croelcotraelc atadleandoecnaorccairncoinmoam caecllesl lbsyb ydidsirsurputpitningg mmitiotocchhoonnddrriiaall ffuunnccttiioonn [[116699]].. Figure 21. Structure of the 6-prenylated isoflavanone lipid Isoangustone A with a summary of its biological activity towards selected cancer targets. The antiproliferation mechanism of 125 has been studied in SW480 human colorectal adenocarcinoma cells [170], prostate cancer cells (PC3, LNCaP, DU 145, and 4 T1) [171,172] and melanoma cells (SK-MEL-2, SK-MEL-5, SK-MEL-28, WM-266-4 cell lines) [171]. Cell cycle arrest and apoptosis via the cessation of cyclin A, cyclin D, cyclin E, CDK2, and CDK4 protein expression and the downregulation of mTOR, PI3 K, Akt, and JNK were the major disrupted pathways identified [171]. Another component of the root of licorice is the isoflavonoid glabridin, 126 from the root of Glycyrrhiza glabra. Compound 126 inhibits cyclooxygenase activity and has an anti- inflammatory and an antiplatelet effect (Figure 22) [173]. Studies in modulating metastatic cascade have demonstrated the efficacy of com- pound 126 via interference of focal adhesion kinase (FAK), proto-oncogene-protein kinase (Src), protein kinase B (Akt), myosin, myosin light chain phosphorylation, and ras homo- log family member A (RhoA) with decreased expression and activities of MMP-9, phos- phorylation of ERK1/2 and JNK1/2 [174]. Molecules 2021, 26, x FOR PEER REVIEW 23 of 50 Figure 20. Structure of the dihydroxyflovanone Liquiritigenin with a summary of its biological ac- tivity towards selected cancer targets. Isoangustone A, 125 is a 6-prenylated isoflavanone lipid molecule isolated from the Molecules 2021, 26,r7o1o34t of Glycyrrhiza (Figure 21). Compound 125 induces apoptosis in SW480 human colo-23 of 48 rectal adenocarcinoma cells by disrupting mitochondrial function [169]. Figure 21. FSitrguucrtue r2e1o.f Sthtreu6c-pturerney olaft ethdeis o6fl-parveanyonlaetleidpi disIosfolanvgaunsotonnee lAipwidit hIsaosaunmgmusatroynoef iAts bwioitlohg aic asluamctmiviatyryto owfa irtdss selected cabnicoelrotgaircgaelt sa.ctivity towards selected cancer targets. The antiprolifTehraetaionnti pmroelcifhearantiisomn m oef c1h2a5n ihsams obfe1e2n5 shtausdbieeedn isnt uSdWie4d8i0n hSWum48a0nh cuomloarneccotalol rectal adenocarcinomadae cneolclasr [c1in7o0m], aprcoelslsta[t1e7 0c]a,npcreors tcaetellcsa (nPcCer3c, eLllNs (CPaCP3,, DLNUC 1a4P5, ,D aUnd14 45 ,Ta1n)d [147T11,1) 7[171,172]and melanoma cells (SK-MEL-2, SK-MEL-5, SK-MEL-28, WM-266-4 cell lines) [1721]] . Cell and melanomacy ccelellasr r(eSsKt a-MndEaLp-o2p, tSoKsis-MviaELth-e5c, eSsKsa-tMionELof-2cy8c, lWin MA,-c2y6c6li-n4 Dc,eclly clilinneEs), C[1D7K12]., aCnedllC DK4 cycle arrest anpdro taepinopextopsreiss svioina atnhde tcheesdsoawtionnre gouf lactyiocnlinof Am,T cOyRc,liPnI 3DK,, cAykctl,iann dE,J NCKDwKe2r,e athnedm ajor CDK4 proteind eisxrpurpetsesdiopnat hawnday tshied ednotiwfiendre[1g7u1l]a. tion of mTOR, PI3 K, Akt, and JNK were Molecules 2021, 26t, hx eF OmRa PjoEErR d RisErVuIEpWteAd npoaththewr caoyms pidoneennttifoiefdth [e1r7o1o]t. of licorice is the isoflavonoid glabridin, 126 from the 24 of 50 Another crooomtpoof nGelnycty orrfh tihzae grloaobrta o. fC liocmorpioceu nisd t1h2e6 iisnohflibaivtos ncyocidlo ogxlaybgreindaisne, a1c2t6iv firtyoman tdheh as an root of Glycyrrahniztia- ignlflaabmram. Catoomrypaonudnadn 1a2n6ti pinlahtiebleittse cffyecclto(oFixgyugreen2a2)se[1 a7c3t]i.vity and has an anti- inflammatory and an antiplatelet effect (Figure 22) [173]. Studies in modulating metastatic cascade have demonstrated the efficacy of com- pound 126 via interference of focal adhesion kinase (FAK), proto-oncogene-protein kinase (Src), protein kinase B (Akt), myosin, myosin light chain phosphorylation, and ras homo- log family member A (RhoA) with decreased expression and activities of MMP-9, phos- phorylation of ERK1/2 and JNK1/2 [174]. FFigiguurere2 2.2S. tSrturcutcutrueroef oafn ainso iflsoafvloanvoindoGidl aGbrlaidbirnidwinit hwaitshu am smuamrymoafryit sobf iiotlso bgiocalolgaicctaivl iatycttiovwityar tdoswards seselelcetcetdedc acnacnecretra rtagregtse.ts. SItusodliieqsuinirmitiond, u1l2a7ti nisg am feltaavsotantiocicda sgcalydceohsaivdeed fermomon sltircaotreidceth peoefsfsiceascsyinogf c ao mbrpoaudn dsp12e6ctrum voiaf ipnthearfremreanccoeloofgfioccaall aacdthiveistiioens kinincalused(iFnAg Ka)n, tpioroxtiod-aonnct,o agnentie--ipnrfolateminmkaitnoarsye, (aSnrcd), apnrotit-edinepres- ksiinoans eaBcti(vAitkite)s,. mCyoomsipno, umnydo s1i2n7l iagnhdt cihtsa ibniopshyonstphheosrizyeladt iodne,riavnadtivrea sishoolmiqouliorgitifna mapiliyoside, m1e2m8,b perreAve(nRth aonAg)iwogitehndeescisre aansedd teuxbper efossrimonatainodn atchtrioviutigehs othf eM iMnhPi-b9i,tpiohno sapnhdo rsyulpatpiornesosfion of EpRrKo1-a/n2gainodgeJnNiKc 1fa/c2to[1r7s 4i]n.cluding MMP-9, placental growth factor, and vascular endothe- lial Igsrooliwquthir iftainc,to12r 7uins daeflra vnoonrmoidoxgilay caoss iwdeelflr oams hlicyoproicxeiap ocsosnesdsiitniognasb broya dimsppeacirtriunmg tohfe hy- pharmacological activities including antioxidant, anti-inflammatory, and anti-depression apctoivxiiati-eisn.dCucoimblpeo fuanctdor1-217αa pnadthitws abyio isny HntTh1e0si8z0e dcedllesr (ivFaigtiuvree i2s3o)li [q1u7i5ri,1ti7n6a].p ioside, 128, prevent angiogenesis and tube formation through the inhibition and suppression of pro- angiogenic factors including MMP-9, placental growth factor, and vascular endothelial Figure 23. Structures of the flavonoid glycoside Isoliquiritin and its biosynthesized derivative isoliquiritin apioside with a summary of their biological activity towards selected cancer targets. An isolate from Glycyrrhiza uralensis, Licoricidin, 129 is another prenylated isoflavo- noid that has been found to inhibit SW480 cells (IC50 7.2 μM) by inducing cycle arrest, apoptosis, and autophagy. It exhibits a range of biological activities including antibacte- rial, anti-aging, and anticancer activities. It is a potential chemopreventive or chemother- apeutic agent against colorectal cancer (Figure 24) [177]. Compound 129 exhibits its anti- carcinogenic effects by inhibiting lung metastasis via suppression of tumor angiogenesis and lymphangiogenesis as well as changing in the local microenvironment of the tumor tissues [178]. It also enhances enhanced gemcitabine-induced cytotoxicity in Osteosar- coma (OS) cells through inactivation of the Akt and NF-κB pathways [179]. The com- pound also blocks UVA-induced photoaging via ROS scavenging and limits the activity of MMP-1 [180]. Molecules 2021, 26, x FOR PEER REVIEW 24 of 50 Figure 22. Structure of an isoflavonoid Glabridin with a summary of its biological activity towards selected cancer targets. Isoliquiritin, 127 is a flavonoid glycoside from licorice possessing a broad spectrum of pharmacological activities including antioxidant, anti-inflammatory, and anti-depres- Molecules 2021, 26, 7134 sion activities. Compound 127 and its biosynthesized derivative isoliquiriti2n4 oafp48ioside, 128, prevent angiogenesis and tube formation through the inhibition and suppression of pro-angiogenic factors including MMP-9, placental growth factor, and vascular endothe- lialg grorwowththfa cftaocrtourn duenrdneorr mnooxrmiaoaxsiwa ealsl aws helylp aosx ihaycponodxiitai ocnosnbdyitiimonpas irbinyg imthpe ahiyrpinogx iath- e hy- poxiniad-uincidbulecfiabclteo rf-a1cαtopra-t1hαw paaytihnwHaTy1 0in80 HceTl1ls0(8F0ig cuerlels2 3(F) i[g17u5r,e1 7263]). [175,176]. FigureF i2g3u.r eSt2r3u.cSttururectsu oref sthofet hfleavflaovnoonidoi dglgylycocossididee IIsoliquiirriititnina nadndit sitbsi obsiyonstyhnetshizeesdizdeedri vdaetriviveaitsiovlieq uisioriltiiqnuaipriotisnid aepwioitshidae with a sumsmumarmy aorfy tohfetihre biriobliogloigciacla al catcitvivitityy ttowardsss seelelectcetdedca cnacnecretar rtgaertgs.ets. AnA insoisloaltaet efrfroomm GGllyyccyyrrrhrhiziazau rualreanlseins,sLisi,c oLriiccoidriinc,id12in9 ,i s1a2n9o iths earnporethneyrla pterdenisyofllaatveodn oisidoflavo- noitad h n a dt thhaats hbeaesn bfeoeunn dautophagy. It efxo touinndhi btoit SinWh4i8b0itc eSlWls (4IC8050 c7e.2llµs M(I)Cby i7n.d2 uμciMnghibits a range of biological activities i5n0 cluding a)n cbyycl einadrrest, apoptibacteriuacl,inangt ic-ay tcolseisging , ,arrest, apoapntdoasinst,i caanndce aruatcotipvhitaiegsy. . IItti sexahpiboittesn tai arlacnhgeem oofp rbeivoelongtiivcealo raccthievmitioetsh einracplueudtiincga gaennttibacte- riala,g aanintis-tacgoilnogre, catnaldc aannctiecra(nFcigeur raec2ti4v)i[t1ie7s7.] .ItC ios ma ppooutnendt1ia2l9 cehxehmiboitps rietsvaennttiicvaerc oinro cgheenmicother- apeeuffteict sabgyenint haigbiatingstl uconglomreecttaaslt acsaisnvceiar s(uFpigpurerses i2o4n)o [f1t7u7m].o Cr oanmgpioogueneds i1s2a9n dexlyhmibpithsa nit-s anti- cargciiongoegneensiics aesffwecetlsl absyc hinahnigbinitginign tlhuenlgo cmalemtaisctraoseins vviriao nsmupenptroefssthioent uomf oturmtisosru easn[g1i7o8g].enesis Molecules 2021, 26, x FOR PEER RaEnVdIItE lWaylms opehnahnangcioesgeennheasinsc eads gweemllc iatas bcihnea-ningdinugc eidn ctyhteo tlooxciacilt ymiincrOosetneovsiarorcnomean(tO oSf) cthelels 2t5u omf 5o0r tisstuherosu [g1h78in].a cItti vaaltsioo neonfhtahnecAesk teannhdanNcFe-dκ Bgpeamthcwitaaybsin[e17-i9n].dTuhceedc ocmyptootuonxdicaitlsyo ibnl oOckssteosar- comUaV A(O-inSd) ucceeldlsp thhortoouaggihn ginvaiacRtiOvaStsiocanv eonfg tihnge aAnkdtl iamnidts tNheF-aκctBiv pityatohfwMaMysP -[11[7198]0. ].The com- pound also blockHsO UVA-indOuced photoaging via ROS scavenging and limits the activity of MMP-1 [180]. OCH3 HO OH Licoricidin, 129 Cancer: Colorectal Cancer: Prostate Cancer Cell: SW480 Cancer Cell: Du-145 Biological Target: CDK1, Akt/mTOR Biological Target: MMP-9 IC50 = 7.2 μM IC50 = 100 μM FFigiguurere2 24.4.S Sttrruucctuturereo of ft htheep prernenylyaltaetdedis iosfloaflvaovnooniodidL iLcoicroicriidcindiwn iwthitah sau smumamryaroyf oitfs ibtsio bloiogliocgalical ac- atcitvivitiyty totowwaarrddss ssellecctted ccancceerr ttaarrggeetsts. . CCoommppouonudnd12 192h9a hsabse beneefno ufonudntod itnoh iinbhititbhiet tmheig mraitgiornataionnd aanddhe asdiohneosifoDnU of1 4D5Uce 1ll4s5 cells iinna ac oconncecnetnrtartaiotino-nd-edpeepnednednetnmt amnnanerntehrr tohurgohutghhe trheed urcetdiounctoiof nM oMf PM-9M, UPr-o9k, iUnarosek-itnyapsee-type PPlalassmmininogoegnenA cAtivcatitvorat(ourP A()u, PVAEG),F ,VinEteGgFri, n-iαn2te, gInrtienr-cαe2ll,u lIanrtAerdcheellsuiolnarM Aoldechuelseio(InC AMMo),lecule (ICAM), and Vascular Cell Adhesion Molecule (VCAM) secretion [178]. Incubation of glycyrol, 130 against human Jurkat cells, arrests the S phase of the cell cycle by activation of the Fas cell surface death receptor (Fas), caspase-8, and caspase-9 proteins but through the JNK pathway in HCT 116 cells [181]. Coumarins are another class of oxygen heterocyclic compounds with diverse bioac- tivities including anti-cancer activities. Licocoumarone, 131 is one of such compounds iso- lated from Glycyrrhiza uralensis. It acts as an apoptosis-inducing agent [182]. The potency of 131 against cancer cell lines, chromatin condensation and nucleus fragmentation has been investigated and found to induce apoptosis (Figure 25) [183,184]. Figure 25. Structures of Glycyrol and Licocoumarone with a summary of their biological activity towards selected cancer targets. Recently, the extensive ethnomedicinal use of plants containing lignans has attracted the interest of many natural product and medicinal chemists. Podophyllotoxin (PTOX), 132, is a lignan produced by various species of Podophyllum genus such as Podophyllum emodi Wall. (syn. P. hexandrum) and Podophyllum peltatum L. (Berberidaceae) [185]. Other genera such as Jeffersonia, Diphylleia, and Dysosma (Family Berberidaceae), Catharanthus (Apocynaceae), Polygala (Polygalaceae), Anthriscus (Apiaceae), Linun (Linaceae), Hyptis (Verbenaceae), Teucrium, Nepeta and Thymus (Labiaceae), Thuja, Juniperus, Callitris and Molecules 2021, 26, x FOR PEER REVIEW 25 of 50 HO O OCH3 HO OH Licoricidin, 129 Cancer: Colorectal Cancer: Prostate Cancer Cell: SW480 Cancer Cell: Du-145 Biological Target: CDK1, Akt/mTOR Biological Target: MMP-9 IC50 = 7.2 μM IC50 = 100 μM Figure 24. Structure of the prenylated isoflavonoid Licoricidin with a summary of its biological ac- tivity towards selected cancer targets. Molecules 2021, 26, 7134 Compound 129 has been found to inhibit the migration and adhesion of D2U5 o1f4458 cells in a concentration-dependent manner through the reduction of MMP-9, Urokinase-type Plasminogen Activator (uPA), VEGF, integrin-α2, Intercellular Adhesion Molecule (ICAM), and Vascular Cell Adhesion Molecule (VCAM) secretion [178]. Incubation of agnldycVyarsoclu, l1a3r0C aegllaAindsht ehsuiomnaMno Jluerckualet (cVeCllsA, Mar)resesctsr etthioen S[ 1p7h8a]s. eIn ocfu tbhaet icoenllo cfygcllyec ybryo la,c1t3iv0ation aogfa tihnest Fhausm cealnl sJuurrfkaactec delelas,tha rrreecsetspttohre (SFapsh)a, sceasopfatshee-8c,e allncdy cclaespbyasaec-t9i vpartoioteninosf bthuet Ftharsough ctehlle sJuNrKfa cpeadthewathayr eince HptCorT( 1F1a6s) c, eclalssp [a1s8e1-]8. , and caspase-9 proteins but through the JNK pathwCaoy in HCT 116 cells [181].Couummarairnisnasr aeraen aonthoetrhcelra scslaosfso oxfy goexnygheetne rhoectyecrloicccyocmlicp ocoumndpsowuinthdsd iwveitrhse dbiivoearcstiev ib-ioac- ttieivsiitniecslu idnicnlgudanintig-c aanntcie-craanctcievri taiecst.ivLiitcioecso. Lumicoarcoonuem, 1a3r1oniseo, n1e31o fiss uocnhe coofm supcohu ncdosmispooluatnedds iso- flraotmedG flryocmyr rGhliyzacyurrrahlieznas iusr.aIltenascitss. aIts aacntsa apso panto asipso-ipntdouscisin-igndaguecnintg[ 1a8g2e].ntT [h1e82p]o. tTenhcey pooftency 1o3f1 1a3g1a iangstacinanstc ecranceclelrl inceelsl, lcihnreosm, cahtirnocmonatdienn csoatniodnenasnadtinounc laenuds fnraugcmleeunst afrtiaognmheanstbaetieonn has ibneveenst iignavteesdtiagnadtefdo uanndd tfooiunnddu cteo ainpdoputcoes iasp(oFpigtuorseis2 (5F)i[g1u8r3e,1 2854)] .[183,184]. FFigiguurere2 52.5.S tSrturcutcutruerseos foGf lGyclycroylroaln danLdi cLoiccooucmouamroanreowneit hwaithsu am smuamrymoafryth oefir tbhieoilro bgicoalol gaicctaivl iatyctivity ttoowwaardrdsss esleelcetcetdedca cnacnecretra rtgaergtse.ts. RReececenntltyl,yt,h teheex etxentesnivseiveet henthonmoemdiecdinicailnuasle uosfep olaf nptlsacnotsn tcaoinnitnaginliinggn alingsnhaanssa httarsa cattetdracted tthheei ninteterersetsto fomf manaynyn antuatrualraplr opdroudctuacnt danmde dmiceidniaclinchale mchiestms.isPtos.d Popodhyolplohtyolxlointo(xPiTnO (XP)T,OX), 113322, ,i sisa al iglingannanp rpordoudcuecdebdy bvya rviaoruisousps escpieescioefs Poofd Popohdyolpluhmyllguemn ugsensuucsh sauschP oadso pPhoydlolupmhyllum eemmooddiiW Walall.l(. s(ysny.nP. .Ph.e hxaexnadnrudmru)ma)n danPdo dPoopdhoypllhuymllupmelt pateultmatLum. ( BLe.r (bBeerirdbaecreidaea)ce[1a8e5) ][.1O85th].e rOther genera such as Jeffersonia, Diphylleia, and Dysosma (Family Berberidaceae), Catharanthus (gAepnoecryan saucecahe )a,sP Joelfyfegrasloan(iPao, lDygipahlayclleeaiae,) ,aAnndt hDriysscoussm(Aa p(Fiaacmeailey) ,BLeinrbuenr(iLdiancaecaeea)e, )C, Hatyhpatriasnthus ((VAerpboecnyancaecaeea),e)T,e uPcorliyugma,laN (ePpoetlaygaanldacTehayem), uAsn(tLharbisicauces a(eA),pTiahcuejaa,e)J,u nLiipneurnus ,(LCianlalicteriasea),n dHyptis T(hVuejorpbseins a(Cceuaper)e, sTsaecuecareiu),mC,a sNsieap(eFtaa baancdea eT)h, yHmapulso p(hLyalbluimac(eRaue)t,a cTehaue)ja, ,C Joumnmipiperhuosra, (CBaullristerirs- and aceae), and Hernandia (Hernandiaceae) have also been reported to produce podophyllotoxin (PTOX) and its derivatives as well as other lignans [185]. Podophyllotoxin, 132 and deoxy- podophyllotoxin, 133, both cyclolignans from the Anthriscus and Juniperus genera have shown excellent therapeutic effect on cancer cells with tubulin, and DNA topoisomerase II as potential targets (Figure 26) [186,187]. Iridoid glycosides are another class of naturally occurring oxygen heterocyclics re- ported to have a variety of biological activities including antidiabetic, antibiotic, anti- inflammatory, and antioxidant activities. They have been found in several plant species including Canthium subcordatum, Alchornea cordifolia, Eucommia ulmoides, and Gardenia species [188–191]. Ginipin 134, Geniposide 135, and Geniposidic acid 136 are iridoid glycosides found in several plants including Eucommia ulmoides, Gardenia jasminoides, and Gardenia fructus (Figure 27). They possess a range of biological activities including anticancer proper- ties. Their mechanisms of action towards cancer include generation of reactive oxygen species, mitochondria dysfunction and cell-cycle regulation as the leading cause of cell death [192,193]. Particularly, compound 134 causes increased levels of Bax in response to p38 MAPK signaling, leading to the initiation of the mitochondrial death cascade [194] whereas compound 135 inhibits hydroperoxide and myeloperoxidase formation caused by 12-O-tetradecanaoylphorbol-13-acetate (TPA) displacement [195,196]. Molecules 2021, 26, x FOR PEER REVIEW 26 of 50 Thujopsis (Cupressaceae), Cassia (Fabaceae), Haplophyllum (Rutaceae), Commiphora (Bur- seraceae), and Hernandia (Hernandiaceae) have also been reported to produce podophyl- lotoxin (PTOX) and its derivatives as well as other lignans [185]. Podophyllotoxin, 132 and deoxy-podophyllotoxin, 133, both cyclolignans from the Anthriscus and Juniperus genera have shown excellent therapeutic effect on cancer cells with tubulin, and DNA topoiso- merase II as potential targets (Figure 26) [186,187]. Molecules 2021, 26, x FOR PEER REVIEW 26 of 50 Thujopsis (Cupressaceae), Cassia (Fabaceae), Haplophyllum (Rutaceae), Commiphora (Bur- seraceae), and Hernandia (Hernandiaceae) have also been reported to produce podophyl- lotoxin (PTOX) and its derivatives as well as other lignans [185]. Podophyllotoxin, 132 and Molecules 2021, 26, 7d13e4oxy-podophyllotoxin, 133, both cyclolignans from the Anthriscus and Juniperus gene ra 26 of 48 Fhiagvuere s h26o.w Sntr uecxtcuerlele onft tthee rcaypcleoulitgicn aenffse cPto odno pchaynlcloetro cxeinll sa nwdi thD etouxbpuoldino,p ahnydll oDtoNxAin twopithoi sao s-um- maerrya osef tIhI eaisr pbiootleongtiicaall taacrtgiveittsy (tFoiwguarrde s2 s6e)l e[1ct8e6d,1 c8a7n]c. er targets. Iridoid glycosides are another class of naturally occurring oxygen heterocyclics re- ported to have a variety of biological activities including antidiabetic, antibiotic, anti-in- flammatory, and antioxidant activities. They have been found in several plant species in- cluding Canthium subcordatum, Alchornea cordifolia, Eucommia ulmoides, and Gardenia species [188–191]. Ginipin 134, Geniposide 135, and Geniposidic acid 136 are iridoid glycosides found in several plants including Eucommia ulmoides, Gardenia jasminoides, and Gardenia fructus (Figure 27). They possess a range of biological activities including anticancer properties. Their mechanisms of action towards cancer include generation of reactive oxygen species, mitochondria dysfunction and cell-cycle regulation as the leading cause of cell death [192,193]. Particularly, compound 134 causes increased levels of Bax in response to p38 MAPK signaling, leading to the initiation of the mitochondrial death casca de [194] Figure 26. SwFtriuhgceuturer ae2so6 f.c tSohtmerucpcytoculuorelni gdonf a1tnh3se5P cioyndcholopiblhigiytnlsla ohntosyx dPinorodanpodpehrDoyelxoloixdtpoeox dianon padhn ydml loDyteooxloxinpowedritohpxahidysulalmosetmo xfaoirnry mwofaittthi oeainr s bucimaoluo-sgeicda l activity towbamyrda 1sry2s e-olOef ct-thteeditrc abndiocleocrgatiancragloe atysc.ltpivhitoyr tboowla-1rd3s- asceleetcatteed (cTanPcAer) tdarigspetlsa. cement [195,196]. Iridoid glycosides are another class of naturally occurring oxygen heterocyclics re- ported to have a variety of biological activities including antidiabetic, antibiotic, anti-in- flammatory, and antioxidant activities. They have been found in several plant species in- cluding Canthium subcordatum, Alchornea cordifolia, Eucommia ulmoides, and Gardenia species [188–191]. Ginipin 134, Geniposide 135, and Geniposidic acid 136 are iridoid glycosides found in several plants including Eucommia ulmoides, Gardenia jasminoides, and Gardenia fructus (Figure 27). They possess a range of biological activities including anticancer properties. Their mechanisms of action towards cancer include generation of reactive oxygen species, mitochondria dysfunction and cell-cycle regulation as the leading cause of cell death [192,193]. Particularly, compound 134 causes increased levels of Bax in response to p38 MAPK signaling, leading to the initiation of the mitochondrial death cascade [194] whereas compound 135 inhibits hydroperoxide and myeloperoxidase formation caused by 12-O-tetradecanaoylphorbol-13-acetate (TPA) displacement [195,196]. Figure 27. SFtriugcuturere 2o7f. tShteruircitduoride ogfly tchoes iidriedsoGiedn giplyinc,oGsiedneipso Gsiedneiapnind,G Geennipiposoisdiidcea cainddw Githenaispuomsimdiacr yacoifdt hweirthb iao lsougmica-l activity towmaradrsys eolfe cthteedirc abniocelor gtaircgael tas.ctivity towards selected cancer targets. Thapsigargin, 137 is a sesquiterpene lactone isolated from the umbelliferous plant, Thapsia gargantea [197]. It has antitumor activity in the low micromolar range when tested in human cancer cell lines. Cytotoxicity effects are generally attributed to imbalance of calcium homeostasis through interference with sarcoplasmic/endoplasmic reticulum Ca2+ ATPase [197]. The compound stimulates MAP kinase signaling via Src and Raf-1. The tumorigenic properties demonstrated by 137 are partially attributed to activation of the Src-MAP kinase pathway [197]. Thapsigargin also induces perturbations in calcium homeostasis and an increase in nitric oxide production eliciting apoptosis and cell death (Figure 28) [198–200]. Farnesiferol C (FC), 138 is a sesquiterpene coumarin isolated from Ferula species (Api- aceae) [201]. It possesses cytotoxic, apoptotic, MDR reversal, antitumor, and antimutagenic properties among other bioactivities (Figure 29). Compound 138 induc es cell cycle arrest Figure 27. Strucatnudrea opfo tphteo isriisdomided gilaytceodsibdyeso Gxiednaitpivine, sGtreensispionsitdhee aMndC FG-e7ncieplolsliidniec [a2c0i2d] w. Iitthis aa slsuomr-eported to mary of their bidoeloacgtiicvaal taecvtiavsitcyu tloarweanrddso tsheelelicatel dg rcoawnctehrf taacrtgoerts(V. EGF)-induced cell proliferation, migration, invasion, and tube formation that is the cause of cancer metastasis [202]. Molecules 2021, 26, x FOR PEER REVIEW 27 of 50 Thapsigargin, 137 is a sesquiterpene lactone isolated from the umbelliferous plant, Thapsia gargantea [197]. It has antitumor activity in the low micromolar range when tested in human cancer cell lines. Cytotoxicity effects are generally attributed to imbalance of calcium homeostasis through interference with sarcoplasmic/endoplasmic reticulum Ca2+ ATPase [197]. The compound stimulates MAP kinase signaling via Src and Raf-1. The tu- Molecules 202m1, 2o6r, ixg FeOnRic P pEErRo pREeVrtIiEeWs demonstrated by 137 are partially attributed to activation of the Src- 27 of 50 MAP kinase pathway [197]. Thapsigargin also induces perturbations in calcium homeo- stasis and an increase in nitric oxide production eliciting apoptosis and cell death (Figure 28) [198–200]. Thapsigargin, 137 is a sesquiterpene lactone isolated from the umbelliferous plant, Thapsia gargantea [197]. It has antitumor activity in the low micromolar range when tested in human cancer cell lines. Cytotoxicity effects are generally attributed to imbalance of calcium homeostasis through interference with sarcoplasmic/endoplasmic reticulum Ca2+ ATPase [197]. The compound stimulates MAP kinase signaling via Src and Raf-1. The tu- morigenic properties demonstrated by 137 are partially attributed to activation of the Src- Molecules 2021, 26, 7134 MAP kinase pathway [197]. Thapsigargin also induces perturbations in calciu2m7 o fh4o8meo- stasis and an increase in nitric oxide production eliciting apoptosis and cell death (Figure 28) [198–200]. Figure 28. Structure of the sesquiterpene lactone Thapsigargin with a summary of its biological ac- tivity towards selected cancer targets. Farnesiferol C (FC), 138 is a sesquiterpene coumarin isolated from Ferula species (Apiaceae) [201]. It possesses cytotoxic, apoptotic, MDR reversal, antitumor, and antimu- tagenic properties among other bioactivities (Figure 29). Compound 138 induces cell cycle arrest and apoptosis mediated by oxidative stress in the MCF-7 cell line [202]. It is also reported to deactiFvFigiagutuerer ve2 a82.s8c.S uStrtluraucrtc uteurneredo oof ftt hhtheeels iesaselqs quguirtioetrewpreptnheen felaa lccattcootnore n(eTV hTEahGpaspFigs)ia-girangridnguiwnc iwethdit ahc esaul lsm upmroamrlyaifreoyfr oaitf-s itbsi obliogloicgailcal ac- tion, migration, inavtcitvaivistiiytoy tnoto,w waanarrdds st suebleec tfeodr mcanaccteieror tntaa rtrghgeeatstts. .i s the cause of cancer metastasis [202]. Farnesiferol C (FC), 138 is a sesquiterpene coumarin isolated from Ferula species (Apiaceae) [201]. It possesses cytotoxic, apoptotic, MDR reversal, antitumor, and antimu- tagenic properties among other bioactivities (Figure 29). Compound 138 induces cell cycle arrest and apoptosis mediated by oxidative stress in the MCF-7 cell line [202]. It is also reported to deactivate vascular endothelial growth factor (VEGF)-induced cell prolifera- tion, migration, invasion, and tube formation that is the cause of cancer metastasis [202]. FigureF2i9g.uSrteru 2ct9u. rSetarusecstquureit ear pseenseqcuoiutemrpareineF acronuemsifaerrionl CFawrnitehstihfeersoulm Cm wariytho fthitse bsiuolmogmicaarlya cotifv iittys tboiwolaorgdiscsaell ected canceratacrtigveittsy. towards selected cancer targets. Rhamnose is a naRthuarmalnlyo soecicsuarrniantgu rdaleloyxoyc csuurgrianrg tdheaot xiys sduegraivr ethda tfriosmde rpivlaendtsfr osumchp laans ts such as Buckthorn, poison sumac, birch trees, and bacteria [203–205]. Among the many applica- Buckthorn, poisotino nss,urmhaamc,n obsiercish ustreedeisn, thaendtr eabtamcetenrtioa f s[k2i0n3–ca2n0c5e]r.. LA-Rmhoanmgn otshee, 13m9aannyd L-fucose, 140 activate apoptosis via the mitochondria pathways particular on the Bcl-2 family pro- teFiingsur[2e0 249,2. 0S5tr]u. cIntuared da itsieosnq,urihtearmpennoes ecoαu-mheadrienr iFna,r1n4e1siifserroelp Co rwteidtht othien hsuibmitmthaery3 .o5f mitsil lbioionlogical PaIc3tKiv/itAy KtoTwpaardthsw sealyecatendd caacntcivera ttearEgRetKs. pathway on breast cancer cells (Figure 30) [206]. Ophiopogonin B, 142 occurs in the herbs Radix O. japonicus, Ophiopogonis radix (ophio- pogonRishraomotn)o, saen dis Oa jnaaptounriacullsy[ 2o0c7c]u.rrItinisg wdiedoexlyy suusgedari nthCath iins edseertirvaeddi tfioronmal mpleadnitcsi nsue.ch as ItBuhacsktahorarnn,g epoofisaonnti csaunmcearcp, robpirecrhti estraegeas,i nsatnvda rbioaucstetryiap es[2o0f3–ca2n05ce].r iAncmluodnign gtlhuen gmany cancer, cervical cancer and gastric cancer [208]. Investigation of changes in intracellular activity of incubated cells with compound 142 using the Western blot method resulted in increased protein expression levels of caspase 3 and B-cell lymphoma 2 (Bcl-2)-associated X protein [208]. Compound 142 also inhibited the proliferation of NPC cells by inducing apoptosis and disturbing the mitochondrial integrity [209]. In addition, compound 142 promotes the expression of mammalian STE20-like kinase 1, large tumor suppressor 1, and Molecules 2021, 26, x FOR PEER REVIEW 28 of 50 applications, rhamnose is used in the treatment of skin cancer. L-Rhamnose, 139 and L- fucose, 140 activate apoptosis via the mitochondria pathways particular on the Bcl-2 fam- ily proteins [204,205]. In addition, rhamnose α-hederin, 141 is reported to inhibit the 3.5 million PI3K/AKT pathway and activate ERK pathway on breast cancer cells (Figure 30) [206]. Molecules 2021, 26, x FOR PEER REVIEW 28 of 50 Molecules 2021, 26, 7134 applications, rhamnose is used in the treatment of skin cancer. L-Rhamnose, 13298 aofn4d8 L- fucose, 140 activate apoptosis via the mitochondria pathways particular on the Bcl-2 fam- ily proteins [204,205]. In addition, rhamnose α-hederin, 141 is reported to inhibit the 3.5 mpihlloiosnp hPoIr3yKla/tAedK-Tas psoactihawteadyp arontdei nac(tYivAaPt)e, sEuRpKp rpesastehswthaey eoxnp rbersesaiosnt coafnYcAePr caenldlst r(aFnigscurriep -30) [2t0io6n].a lly enhances associate domains in NPC cells (Figure 31) [209]. Figure 30. Structures of deoxy sugars L-Rhamnose, L-Fucose, and rhamnose β-hederin with a summary of their biological activity towards selected cancer targets. Ophiopogonin B, 142 occurs in the herbs Radix O. japonicus, Ophiopogonis radix (ophi- opogonis root), and O japonicus [207]. It is widely used in Chinese traditional medicine. It has a range of anticancer properties against various types of cancer including lung cancer, cervical cancer and gastric cancer [208]. Investigation of changes in intracellular activity of incubated cells with compound 142 using the Western blot method resulted in in- creased protein expression levels of caspase 3 and B-cell lymphoma 2 (Bcl-2)-associated X protein [208]. Compound 142 also inhibited the proliferation of NPC cells by inducing apoptosis and disturbing the mitochondrial integrity [209]. In addition, compound 142 promotes the expression of mammalian STE20-like kinase 1, large tumor supp ressor 1, FigFuigreu r3e0.3 S0.trSutrcutuctruerse osfo dfedoexoyxa ysnusdug gaparshr soLLs-R-pRhhaoamrynnlaootssed,, L-a--Fssuoccoisaet,,e adn dp rrhohatameminno os(esYeβA β-Ph-he),de desreuirnpinpw rwiethistshae sau stmuhme amerxyaproyrfe otshfs etiihorenbi rio blfoi ogYliocAagPlic aaln d actaivctiitvyi ttyowtoawrdarsd ssesleelcetcetde dcacnanctecrrea rtnatsarcgrrgeietptsst. .ionally enhances associate domains in NPC cells (Figure 31) [209]. Ophiopogonin B, 142 occurs in the herbs Radix O. japonicus, Ophiopogonis radix (ophi- opogonis root), and O japonicus [207]. It is widely used in Chinese traditional medicine. It has a range of anticancer properties against various types of cancer including lung cancer, cervical cancer and gastric cancer [208]. Investigation of changes in intracellular activity of incubated cells with compound 142 using the Western blot method resulted in in- creased protein expression levels of caspase 3 and B-cell lymphoma 2 (Bcl-2)-associated X protein [208]. Compound 142 also inhibited the proliferation of NPC cells by inducing apoptosis and disturbing the mitochondrial integrity [209]. In addition, compound 142 promotes the expression of mammalian STE20-like kinase 1, large tumor suppressor 1, and phosphorylated-associated protein (YAP), suppresses the expression of YAP and transcriptionally enhances associate domains in NPC cells (Figure 31) [209]. FFiigguurree3 311. .S Strtuructcuturereo fotfh tehsea psaopnoiniOnp OhpiohpiogpongionnBinw Bit hwaitshu am smuamrymoafriyts obfi oitlso gbiicoalloagcictiavli tayctiovwitayr dtos- swelaercdtesd seclaencctedr tcaarngceetsr. targets. The anti-cancer properties of some oxygen heterocyclics of marine origin and their mechanism of action have also received attention in recent times. The molecular mecha- nisms by which some of these marine natural products activate apoptosis mainly include dysregulation of the mitochondrial pathway, the activation of caspases, and/or increase of death signals through transmembrane death receptors [210]. Mitogenic roles of VEGF and modulation of the NF-κB pathway have been demonstrated to be the major underlying mechanism of action [211–213]. Fucoxanthin, 143 is a naturally occurring brown- or orange-colored pigment that belongs to the class of non-provitamin A carotenoids present in the chloroplasts of brown seaweeds [214]. Anti-proliferative and cancer preventing properties of compound 143 and its derivative fucoxanthinol, 144 are medi ated through different signaling pathways, Fiignucrlue d3i1n. gSttrhuecctuarsep aosfe tsh,eB scal-p2opnrinot Oeipnhs,ioMpAogPoKn,inP IB3 Kw/itAhk at ,sJuAmKm/aSrTyA oTf, AitsP b-1io, lGogAiDcaDl a4c5t,ivanitdy to- wsaervdesr saelleocttheedr cmanocleerc utalergsetthsa. t are involved in cell cycle arrest, apoptosis, anti-angiogenesis, or inhibition of metastasis (Figure 32) [214]. Molecules 2021, 26, x FOR PEER REVIEW 29 of 50 The anti-cancer properties of some oxygen heterocyclics of marine origin and their mechanism of action have also received attention in recent times. The molecular mecha- nisms by which some of these marine natural products activate apoptosis mainly include dysregulation of the mitochondrial pathway, the activation of caspases, and/or increase of death signals through transmembrane death receptors [210]. Mitogenic roles of VEGF and modulation of the NF-κB pathway have been demonstrated to be the major underly- ing mechanism of action [211–213]. Fucoxanthin, 143 is a naturally occurring brown- or orange-colored pigment that be- longs to the class of non-provitamin A carotenoids present in the chloroplasts of brown seaweeds [214]. Anti-proliferative and cancer preventing properties of compound 143 and its derivative fucoxanthinol, 144 are mediated through different signaling pathways, in- Molecules 2021, 26, 7134 cluding the caspases, Bcl-2 proteins, MAPK, PI3K/Akt, JAK/STAT, AP-1, GADD4259, oafn4d8 several other molecules that are involved in cell cycle arrest, apoptosis, anti-angiogenesis, or inhibition of metastasis (Figure 32) [214]. FFiigguurree 3322.. SSttrruuccttuurreess ooff tthhee nnoonn--pprroovvitiatammininA Ac acarorotetnenoiodidF uFcuocxoaxnatnhtihnina nadndit sitds edreivriavtiavteivFeu Fcuocxoaxnathnitnhoinl owl iwthitahs au msummamryaroyf tohfe tihrebirio bloiogliocgailcaaclt aivcittiyvittoyw toawrdasrdsesl escetleedctecdan ccaenrctearr gtaertgs.ets. Caarrrraageeeenaanss aarree lliineeaarr ssullffaatteed pollyssaacccchaarriideess eexxttrraacctteed ffrrom maarriinee rreed aallgaaee,, Kaappaaphyccuss ssttrriiaattum [[215]].. The ccoassttall rregiion off Senegall and tthe Gambiia,, whiicch iiss tthe brreediing grround fforr herrrriings iin Westt Affrriica,, iis saiid tto be verry rriich iin rred allgae,, whiich allso serves as ffood fforr tthhee yyoouunngg hheerrrininggss [2[21166,2,21177].] .TThhee SSeennegegamambbiainan cocaosats itsi sthtehreerfeofroer ea ma majoarjo srousorcuer coef roafwra mwatmeraitaelr fioarl tfhoer pthroedpurcotdiounc toiof ncaorrfacgaerernaagnese,n wanhsic,hw ahriec uhsaerde aus seexdciaps- ieexnctisp inen tthsei nfotohde afonodd pahnadrmpahcaerumtiaccael uintidcualstirnidesu [s2tr1i7e–s2[2201]7. –H2o20w].evHeor,w itesv uesr,e ihtsaus sine hreacseinnt triemc ens tetliimciteesde cliocnitseidecroanbsleid ceornabtrloevceornsytr oinv evriseywi nofv iitesw peorfceitisvepde rhceairvmefdulh eafrfmecftusl. eRfefececntst. iRnevceesntitgiantvioenstsi ghaatvioen sshhoawvne tshhaotw thnist hcalatstsh oisf cploalsyssoafccphoalyrisdaecsc hpaorsisdeessepso asnsetiscsaenscaenr tpicraonpceerr- ptireosp. eTrhtiee sc.aTrrhaegceaernrangse ecnoannssiscto onfs iasltteorfnaalteinrnga 3ti-nlignk3-eldin βk-eDd-gβa-Dla-cgtaolsaec taonsed a4n-dlin4k-leidnk ae-dD-ag-Da- lgaacltaocsteo soero 4r-l4i-nliknekde d3,36,-6a-nahnyhdyrdor-oD--Dg-aglaalcatcotsoes.e T. Thhe ecacarraraggeeennaann ooliliggoossaacccchhaarriideess exert their anticancer properties by promoting the immune system [221]. The effects of carrageenan olliigosacchariides on transpllantablle tumors and macrophage phagocytosiis,, quanttiitatiive hemollysiis off sheep red bllood celllls ((QHS)),, llymphocytte prolliifferattiion,, tthe acttiiviitty off natturall kiillllerr ccellllss ((NK)),, prroduccttiion off iintterrlleukiin--2 ((IIL--2)) and ttumorr neccrrossiiss ffaccttorr--a ((TNF--a)),, haavee beeeen ssttuuddiieedd [[221155]]. .ThTehye yinihnihbiibt itthteh gergorwotwh tohf otrfatnraspnlsapnltaanbtlaeb slearscaormcoam Sa18S01 a8n0da nind- cinrecaresae sme amcraocprohpahgae gpehpaghoagcyotcoystios,s issp, lsepelne elynmlypmhopchyotec ypteroplirfoerliafteiroant,i oNnK, N ceKllsc ealclstivaicttyiv, istey-, rsuermuaml-aIlL-I-L2 -a2nadn dTNTNF-Fa- alelveevle linin SS118800-b-beeaarriningg miiccee [[221155,,222211]].. SSuullpphhaatteedd ggaallaaccttooppyyrraannoossyyll Molecules 2021, 26, x FOR PEER REVλλIE,, W1144 55 aanndd κκ,, 114466 ccaarrrraaggeeeennaann hhaavvee bbeeeenn ffoouunndd ttoo iinnhhiibbiitt tthhee pprroolliiffeerraattiioonn ooff bbrreeaasstt,, cc3oo0ll ooofnn 5,,0 lliivveerr,, aanndd oosstteeoossaarrccoomaa cceellll lliinneess bbyy uupprreegguullaattiinngg pprrooaappooppttoottiicc ffaaccttoorrss CCaassppaassee--33,,99 aanndd 88 wwiitthh ddeepprreessssiioonn ooff bbaaxx//bbaall--22 rraattiioo ((FFiigguurree 3333)) [[221155,,222211]].. FFiigguurree3 333.. SSttrruuccttuurreesso off SSuullpphhaatteedd ggaallaaccttooppyyrraannoossyyllL Laambbddaa--CCaarrraaggeeennaanna annddK Kaappppaa-C-Caarrraaggeeennaann wwitihtha as suummmmaaryryo offt htheeirirb bioiolologgicicaal la acctitvivitiytyt otowwaardrdsss esleelcetcetdedc acanncecrert atragrgetest.s. FFuuccooididaann, ,1 14477i sisa ap oploylsyascacchcahraidriedlea rlgaerlgyelmy amdeaduep uopf Lo-f uLc-ofusecoasned asnudlf astuelfgartoeu gprsoiusop-s laistoeldatferodm frbormow bnroawlgnae aolrgasea ocru csuema bcuercsu,msubcehrsa,s sLuacmhi naasr iaLadmigintaatrai,aA dsicgoiptahtyal,l uAmscnoopdhoyslulumm, Mnoadcorosucyms,t iMs paycriofceyras,tiFs upcyursifvereas,i cFuulocsuuss v, easnicdulmosaunsy, aontdh emrsa(nFyig outrhee3rs4 )(F[2ig2u2]r.eC 3o4m) [p2o2u2]n. dC1o4m7- epxohuibnidts 1a47r aenxgheiboitfs bai oranctgiev iotife bsioinacltuivdiitniegs ainctliuoxdiidnagn atn, tainotxii-dtuamnto, ar,natin-tui-mcooarg, ualnatni-tc,oaangtui-- tlharnotm, abnottii-cth, irmombuontoicr,e igmumlautonroyr,eagnutil-avtoirrayl,, andti-avnirtai-li,n aflnadm amntait-oinrfylaemffemcatsto[r2y2 2e]f.feTchtes c[2o2m2]-. The compound inhibits cancer cells through activating apoptosis. It is reported to increase the levels of reactive oxygen species (ROS), and induce an increase in ATF4, CHOP, and ER stress via modulation of Toll-like receptor 4 in lung cancer cells, leading to apoptosis and inhibition of cell proliferation [223]. It is further reported to induce apoptosis in MDA- MB-231 of breast cancer cells as well as activate caspase-8 and -9 in MCF-7 and HeLa cells [224]. Figure 34. Structure of the polysaccharide Fucoidan with a summary of its biological activity to- wards selected cancer targets. Frondaside A, 148 is a triterpenoid glycoside from the Atlantic Sea Cucumber, Cucu- maria frondose [225]. Cucumarioside A2-2, 149 is also a triterpene glycoside isolated from the Far-Eastern edible sea cucumber, Cucumaria japonica [226]. Both compounds have a broad spectrum of anti-cancer effects, including induction of cellular apoptosis. They in- hibit cancer cell growth, migration, invasion, formation of metastases, and angiogenesis [225]. Their cytotoxicity is reported to be through induction of apoptosis by modulation of diverse apoptosis related proteins such as caspase 3, 8, and 9, PARP, and DNA frag- mentation [226–228]. Both compounds 148 and 149 suppress cell proliferation, increase stress related proteins like the Janus kinase and p38 mitogen-activated protein kinase as Molecules 2021, 26, x FOR PEER REVIEW 30 of 50 Figure 33. Structures of Sulphated galactopyranosyl Lambda-Carrageenan and Kappa-Carrageenan with a summary of their biological activity towards selected cancer targets. Fucoidan, 147 is a polysaccharide largely made up of L-fucose and sulfate groups isolated from brown algae or sea cucumbers, such as Laminaria digitata, Ascophyllum nodosum, Macrocystis pyrifera, Fucus vesiculosus, and many others (Figure 34) [222]. Com- Molecules 2021, 26, 7134 pound 147 exhibits a range of bioactivities including antioxidant, anti-tumor, a3n0toif-c48oagu- lant, anti-thrombotic, immunoregulatory, anti-viral, and anti-inflammatory effects [222]. The compound inhibits cancer cells through activating apoptosis. It is reported to increase ptohuen ldevinelhsi boift srceaancctievrec eolxlsytghernou sgpheacicetisv (aRtiOngS)a,p aonpdto isnisd.uItceis arenp ionrcteredatsoei ninc rAeaTseF4th, eClHevOelPs, and oEfRre satcrteivses ovxiay gmenodspuelaciteiosn(R oOf ST),oalln-dlikined ruecceepantoirn 4cr iena sleuinngA cTaFn4c,eCr HceOllPs,, alneaddEiRngs ttroe saspvoiaptosis manodd uinlahtiiobnitioofnT oolfl c-leiklle prreocleipfetroart4ioinn [l2u2n3g].c Iatn icse frucrethlles,r lreeapdoinrgtetdo taop ionpdtuoscies aapnodpitnohsiibsi itnio Mn DA- oMf cBe-l2l3p1r oolfi fberreaatisot nca[n22c3e]r. cIetlilss fausr wtheelrl raesp aocrttievdatteo ciansdpuacsee-a8p aonpdto -s9is inin MMCDFA-7- ManBd- 2H31eLoaf cells b[r2e2a4s]t. cancer cells as well as activate caspase-8 and -9 in MCF-7 and HeLa cells [224]. FFiigguurere3 43.4S. tSrutrcutuctrueroef tohfe tphoel ypsoalcycshacrcidheaFriudceo iFduacnowiditahna wsuitmhm aa sruymofmitsarbyio olofg iitcsa lbaioctliovgitiycatol wacatridvsity to- swelaecrtdesd scealneccteerdt acragnectse.r targets. FFrroonnddaasisdideeA A, ,1 41848is isa at rtirtietreprpeneoniodidg lgylcyocsoidsiedfer ofrmomth tehAe tAlatnlatnictiSce SaeCa uCcucmubmebr,eCr,u C- ucu- cmumarairai afrfornodnodsoes e[2[2252]5.] .CuCcuucmumarairoisoisdide eAA2-22-2, ,141949 isi salasloso a atrtirtietreprpeennee gglylyccoossididee isisoollaatteedd from ftrhoem Ftahre-EFaars-tEearsnt eerdniebdleib sleeas ecauccuucmumbebre,r ,CCuuccuummaarriiaa jjaappoonniiccaa[ 2[22266].].B Botohthco cmopmopuonudnsdhsa vheave a abbroroaadd ssppeecctrtruumm ooff aannttii--ccaanncceerr eeffffeeccttss,, iinncclluuddiinngg iinndduucctitoionno of fc eclellululalrara papopotpotsoissi.sT. hTehyey in- ihnihbiibti tcacanncceer rcceellll ggrroowwtthh,, mmiiggrraattiioonn,, iinnvvaassioionn, ,f oformrmataitoionno fomf meteatsatasstaesse, sa,n adnadn ganiogene-Molecules 2021, 26, x FOR PEER REVIEW giogenesis s[i2s2[522].5 T].hTehire icryctyottootoxxicicitiyty iiss rreeppoorrtteedd ttoob beet hthroruoguhghin dinudcution of apoptosis b 3y1 mof 50 ction of apoptosis boyd muloatdiounlation of diverse apoptosis related proteins such as caspase 3, 8, and 9, PARP, and DNA fragmen- toafti odniv[e2r2s6e– 2a2p8o]p. Btoostihs croemlapteodu npdros t1e4i8nsa nsduc1h4 9ass ucpapspreasssec 3el,l 8p, raonlidfe r9a, tPioAn,RiPn,c raenadse DstNreAss frag- rmelaetnetdatpiornot e[2in2s6–li2k2e8t]h. eBJoatnhu csokminpaosuenadnsd 1p4388 amnidto 1g4e9n -saucptipvaretesds cperlolt epirnokliifnearasetioans ,w inelclrease well as induce acssetrlilen scdsyu crceleela cateerllrdec ysptcr lovetieaair ndreses cltirkveeiaa stdhee eic nJr aecnaesulels i cnkyiccnelaelsl-erce yalcnaletde- rdpe l3pa8tr eomdteiptiornogste,e nsin-uascc,htsi uvacash tceaydsc pcliyrnco lAtien inA kainndase as and cyclin B (Fcigyuclrine B35()F i[g2u2r9e,23350)][.2 29,230]. Figure 35.FSigtrurcetu 3re5s. Sotfrturicteturprens ooifd tgrilytecropsiedneosiFdr ognlydcaosisdiedeAs aFnrdonCduacusimdaer Aio saidnedA C2u-2cuwmitharaiossuimdem Aar2y-2o fwthiethir ab isoulomg-ical activity tomwardys osfe ltehceteird bciaonlcoegritcaarlg aetcst.ivity towards selected cancer targets. Ds-echinoside A, 150 isolated from Pearsonothuria graeffei is a non-sulfated triterpene glycoside derived from the desulfurization reaction of echinoside A [231]. Philinopside A, 151 and Philinopside E, 152 on the other hand are sulfated saponins isolated from the sea cucumber, Pentacta quadrangulari (Figure 36) [232,233]. The three compounds all possess a variety of biological activities including antifungal, hemolytic and membranotropic action as well as antiproliferative effects against various human cancer cell lines [234]. They re- duce cancer cell adhesion, cell migration, and tube formation [231,235]. Specifically, com- pounds 151 and 152 reduced the tumor volume by triggering apoptosis of both tumor and tumor-associated endothelial cells via inhibition of angiogenesis-related receptor tyrosine kinases including VEGFR2, FGFR1, and EGFR [232,233]. While compounds 151 and 152 significantly inhibit the proliferation, migration, and tube formation of human microvas- cular endothelial cells (HMECs) [232,233], 150 on the other hand inhibits the proliferation of human hepatocellular carcinoma cells via MMP9, TIMP-1, and VEGF expression [231]. Figure 36. Structures of a non-sulfated triterpene glycoside Ds-Echinoside A and two sulfated saponins Philinopside A and Philinoside E with a summary of their biological activity towards selected cancer targets. Molecules 2021, 26, x FOR PEER REVIEW 31 of 50 well as induce cell cycle arrest via decrease in cell cycle-related proteins, such as cyclin A and cyclin B (Figure 35) [229,230]. Molecules 2021, 26, 7134 Figure 35. Structures of triterpenoid glycosides Frondaside A and Cucumarioside A2-2 wi3t1ho af 4s8um- mary of their biological activity towards selected cancer targets. DDs-se-cehchininoossididee AA,, 115500 iissoollaatteedd ffrroomm PPeeaarrssoonnooththuuriraiag rgareafefeffieiis ias na onno-nsu-slfualtfeadtetdri tterritpeernpeene glgylcyocsoisdidee ddeerirviveedd ffrroomm tthhee ddeessuullffuurriizzaattiioonnr reeaacctitoionno of fe cehchinionsoisdiedAe A[2 [3213].1P].h PilhiniloinposipdseidAe, A, 15115 1anandd PPhhiliilninooppssiiddee EE,, 115522 oonn tthhee ootthheerr hhaanndda areres usulflaftaetdeds aspaopnoinnisniss oislaotleadtefdro fmrotmhe thseea sea cuccuucmumbbere,r ,PPeennttaaccttaa qquaadrraangullaarrii ((Fiiguurree3 366))[ 2[23322,2,323]3.]T. Theheth trhereeceo cmompopuonudnsdasll apllo spsoesssseass a vavraireiteyty oof fbbioiolologgicicaall aaccttiiviittiies including anttiiffuunnggaal,l,h heemmoolyltyictica nadndm memembrbarnaontrootproicpaict aiocntion asa swwelel lal sa sanatniptirporloilfiefreartaitvivee efeffefecctsts aaggaaininsst tvvaarrioiouuss hhuumaann ccaanncceerr cceellll lliines [[234]. TThheeyy re- durecdeu ccaencaenr cerll caedllhaedsihoens,i ocnel,l cmelilgmraitgiroant,i oan,da tnudbetu fboermfoartmioant i[o2n31[2,23315,2].3 5S]p.eScipfeiccaifillcya, lclyo,m- pocoumndpso u15n1d san15d1 1a5n2d re1d52urceedu tcheed ttuhme oturm voorluvmoleu mbye tbryigtgriegrginegri nagpoapotopstioss oisf obfobthot thutmumoro arnd tuamndort-uasmsoocr-iaastesodc eiantdedotheneldiaolt hceellilasl vcieal lisnhviibaitiinohni boift iaonngioofgaenngeisoigs-erneelasitse-dre rleacteedptroerc teyprtoosrine kitnyarosessin ienkcliunadsiensgi nVcEluGdFinRg2,V FEGGFFRR12,, aFnGdF REG1,FaRn d[2E3G2,F2R33[]2.3 W2,2h3i3le]. cWomhipleocuonmdps o1u5n1d asn1d5 1152 siagnndifi1c5a2nstliyg ninifihciabnitt ltyhein phriboiltiftehreatpioronl,i fmeriagtriaotnio, nm, iagnradt itounb,ea fnodrmtuabteiofno romf ahtuiomnaonf mhuicmroanvas- cumlaicr reonvdaoscthuelalriael ncdelolsth (eHliMalEcCelsls) [(2H3M2,2E3C3s]), 1[25302 o,2n3 3th],e1 o5t0heorn htahnedo itnhheribhitasn tdhein phriobliitfserthateion ofp hroulmifearatioexpressnio hne npaotfohuman hep[231].cellular carc aitnoocmellau claerllsc avricain MomMaPc9e, lTlsIMviPa-1M, ManPd9 V, TEIGMFP e-1x,parensdsiVonE G[2F31]. FigFuirgeu r3e6.3 6S.trSutrcutuctruerse soof faa nnoonn--ssullffaatteed ttrriitteerrppeenneeg lgylcyocsoidsiedDe sD-Esc-hEicnhoisnidoseiAdea nAd atnwdo tswulofa steudlfsaatpedon sianps oPnhiinlisn oPphsiildineoApsaindde A andP hPihliinlionsoidseidEe wE iwthitahs ua msummamryaorfyt hoef itrhbeiiorl bogioicloagl aiccatilv aitcytivtoiwtya trodws saerldesc tseedleccatnecde rcatanrcgeert st.argets. The Luzonicosides (Luzonicoside A), 153 and Luzonicoside D, 154 are cyclic steroidal glycosides from the starfish Echinaster luzonicus. They affect cell cycle regulation and apoptosis by inhibiting proliferation, the formation of colonies, and the migration of SK- Mel-28 cells [236]. Aragusterol A, 155 on the other hand is a steroidal epoxide isolated from Okinawan sponge of the genus, Xestospongia [237]. It has been established that cell-cycle hindrance by 155 is dependent on the reduced expression of cyclin-dependent kinase (CDK)s and cyclins involved in the G1-S transition such as CDK2, CDK4, cyclin D1, A, and E (Figure 37) [237]. Heteronemin, 156 is a sesterterpene isolated from the sponge Hyrtios sp [238]. It possesses a pentacyclic scalarane skeleton including a dihydrofuran moiety. Compound 156 induces apoptosis in prostate lymph node carcinoma of the prostate (Lncap) cells via oxidative and ER stress, coupled with the inhibition of topoisomerase II and Hsp90 when evaluated against K652 cells, targeted NF-κB upstream protein mitogen-activated protein kinase (MAPK), and engineered tumor necrosis factor (TNF)-α-mediated apoptosis [239]. It also promotes apoptotic cell death by inhibiting the phosphorylation of p38 MAPK (Figure 38) [239]. Nagilactone E, 157, a dinorditerpenoid isolated from Podocarpus nagi [240] upregulates the expression of programmed death-ligand 1 (PD-L1) in lung cancer cells through the acti- vation of jun N-terminal kinases (JNK)-c-Jun axis, which has the potential to combine with the PD-1/PD-L1 antibody therapies in lung cancer [240]. It also suppresses transforming growth factor beta 1 (TGF-β1) stimulated cell migration and invasion. It is also a pur- Molecules 2021, 26, x FOR PEER REVIEW 32 of 50 The Luzonicosides (Luzonicoside A), 153 and Luzonicoside D, 154 are cyclic steroidal glycosides from the starfish Echinaster luzonicus. They affect cell cycle regulation and apoptosis by inhibiting proliferation, the formation of colonies, and the migration of SK- Mel-28 cells [236]. Aragusterol A, 155 on the other hand is a steroidal epoxide isolated from Okinawan sponge of the genus, Xestospongia [237]. It has been established that cell- cycle hindrance by 155 is dependent on the reduced expression of cyclin-dependent kinase Molecules 2021, 26, x FOR PEER REVIEW (CDK)s and cyclins involved in the G1-S transition such as CDK322, oCf 5D0 K4, cyclin D1, A, and E (Figure 37) [237]. The Luzonicosides (Luzonicoside A), 153 and Luzonicoside D, 154 are cyclic steroidal glycosides from the starfish Echinaster luzonicus. They affect cell cycle regulation and Molecules 2021a,p26o, p71t3o4sis by inhibiting proliferation, the formation of colonies, and the migration of SK- 32 of 48 Mel-28 cells [236]. Aragusterol A, 155 on the other hand is a steroidal epoxide isolated from Okinawan sponge of the genus, Xestospongia [237]. It has been established that cell- cycle hindrance by 155 is dependent on the reduced expression of cyclin-dependent kinase ported protein synthesis inhibitor with strong binding towards serine/threonine-protein (CDK)s and cycliknins aisnev(oRlIvOeKd) 2in[ 2t4h1e,2 4G21].-SF utrrtahnesrimtioorne ,scuocmhp aosu nCdD1K572,i nChDibKits4,b ocythclcianp D-d1e,p eAn,d ent and and E (Figure 37)c [a2p3-i7n]d. ependent translations (Figure 38) [241]. Figure 37. Structures of cyclic steroidal glycosides Luzonicoside A, Luzonicoside D, and a steroidal epoxide Aragusterol A with a summary of their biological activity towards selected cancer targets. Heteronemin, 156 is a sesterterpene isolated from the sponge Hyrtios sp [238]. It pos- sesses a pentacyclic scalarane skeleton including a dihydrofuran moiety. Compound 156 induces apoptosis in prostate lymph node carcinoma of the prostate (Lncap) cells via oxi- dative and ER stress, coupled with the inhibition of topoisomerase II and Hsp90 when evaluated against K652 cells, targeted NF-κB upstream protein mitogen-activated protein kinase (MAPK), and engineered tumor necrosis factor (TNF)-α-mediat ed apoptosis [239]. FigureF3i7g. uStrreu 3ct7u.r SestroufcctyucrleiIcst s oatefl rscooyid cpalilrcog slmytecroosteidsea sal pLguolyzpoctnooisctioidcsei dcs eLlAul ,dzLoeunazitochon sibcioyds eiid nAeh,D iLb,uiatzniodnngai csttoheserio dpideha Dol es, paonhxdoid raey sAltaeratrigoouidnsta eolr fo lpA38 MAPK (Fig- with a esupmoxmidarey Aofrathgeuirstbeirooluol grAiec aw3l8iat)ch t[i va2i 3sty9u]mt.o wmaarrdys osefl ethcteeidr cbainocloergtiacragl eatsc.tivity towards selected cancer targets. Heteronemin, 156 is a sesterterpene isolated from the sponge Hyrtios sp [238]. It pos- sesses a pentacyclic scalarane skeleton including a dihydrofuran moiety. Compound 156 induces apoptosis in prostate lymph node carcinoma of the prostate (Lncap) cells via oxi- dative and ER stress, coupled with the inhibition of topoisomerase II and Hsp90 when evaluated against K652 cells, targeted NF-κB upstream protein mitogen-activated protein kinase (MAPK), and engineered tumor necrosis factor (TNF)-α-mediated apoptosis [239]. It also promotes apoptotic cell death by inhibiting the phosphorylation of p38 MAPK (Fig- ure 38) [239]. FFigiguurere3 83. 8S.t rSutcrturcetsuoref sth oefs etshter tseerspteenreteHrpeteenroen Hemeitneraonndetmheind inaonrd ittehrep ednionidorNdaitgeilrapcetonnoeidE wNiathgilactone E awsuitmh ma asruymofmthaeriyr boifo tlhogeiicra bl iaocltoivgiitcyatlo awcatrivdistsye lteocwteadrcdasn scerletcatregdet sc.ancer targets. Marine sponges are known to be a rich source of bioactive natural products. Stelletta, a genus of white marine sponges (Class Demospongiae) is a very rich source of diverse and complex biologically relevant natural products, including alkaloids, terpenoids, peptides, lipids, and steroids. Compounds isolated from this genus include the isomalabaricane-type terpenoids Stelletin A 158, from the marine sponge Stelletta tenuis and Stelletin B, 159 isolated from Jaspis stellifera. The compounds trigger cytoprotective activity through the upregulation of proapoptotic Bax-type (Bak and Bax) protein l evels, downregulation of Figure 38. StructurBecsl -o2f Athket isnehsitbeirttieornpienneA 5H4e9t,eKro5n6e2manind aKnUd8 t1h2ec edlilnso(Frdigituerrep3e9n)o[i2d4 3N].agilactone E with a summary of their biological activity towards selected cancer targets. Molecules 2021, 26, x FOR PEER REVIEW 33 of 50 Nagilactone E, 157, a dinorditerpenoid isolated from Podocarpus nagi [240] upregu- lates the expression of programmed death-ligand 1 (PD-L1) in lung cancer cells through the activation of jun N-terminal kinases (JNK)-c-Jun axis, which has the potential to com- bine with the PD-1/PD-L1 antibody therapies in lung cancer [240]. It also suppresses trans- forming growth factor beta 1 (TGF-β1) stimulated cell migration and invasion. It is also a purported protein synthesis inhibitor with strong binding towards serine/threonine-pro- tein kinase (RIOK)2 [241,242]. Furthermore, compound 157 inhibits both cap-dependent and cap-independent translations (Figure 38) [241]. Marine sponges are known to be a rich source of bioactive natural products. Stelletta, a genus of white marine sponges (Class Demospongiae) is a very rich source of diverse and complex biologically relevant natural products, including alkaloids, terpenoids, pep- tides, lipids, and steroids. Compounds isolated from this genus include the isomalabari- cane-type terpenoids Stelletin A 158, from the marine sponge Stelletta tenuis and Stelletin Molecules 2021, 26, 7134 B, 159 isolated from Jaspis stellifera. The compounds trigger cytoprotective activity thr3o3uofg4h8 the upregulation of proapoptotic Bax-type (Bak and Bax) protein levels, downregulation of Bcl-2 Akt inhibition in A549, K562 and KU812 cells (Figure 39) [243]. Fiigurree 3399.. SSttrruuccttuurreess ooff tthee iissomaallaabbaarriiccaannee--ttyyppee tteerrppeennooiiddss SStteelllleettttinin A aanndd B and a peenttaccycclliicc guaniidiinee allkalloiid CCrraammbbeesscciiddiinn 880000 wwiitthh aa ssuummmmaarryy ooff tthheeiirr bbiioollooggiiccaall aaccttiivviittyy ttoowwaarrddss sseelleecctteedd ccaanncceerr ttaarrggeettss.. Crraambbeesscciiddiinn 88000, ,16106,0 ,isi sa apepnetnactaycylicl igcugaunaidniindein aelkaallkoaidlo isdoliasoteldat efrdomfr otmhe tmhearminae- srpinoengspe oMnogneanMchonoraan vchiroidraisv [i2r4id4i]s. I[t2 i4n4d].ucItesin cdelul ceysclcee allrrceysctl aenadrr aepsot pantodsiasp ino ptrtiopslies-ninegtaritpivle- bnreegaasti vcaenbcrera sctelclasn. cIte ralcseol las.ctIitvaaltseos apc5ti3v, awtehsipch5 3i,nw tuhricnh ininacttuirvnatiensa cCtDivKat1e,s rCesDuKlt1in, gre isnu lcteinllg- ciynccle lal-rcryecstle [2a4r4re–s2t4[62]4. 4C–r2a4m6]b.esCcriadminb 8e0s0c idpirnot8e0ct0s pHroTt2e2c tcseHllsT a2g2acinelslts galguatainmstatgel-uintadmucaetde- oinxidduacteivde otxoixdicaittiyv eantodx ipcriotyteacntsd HpTro2t2e catnsdH nTe2u2roabnldasntoemurao bcelallsst ofrmoamc tehlles ofrxoidmattihve ostxriedsas- itnivdeucsetrde sbsyi nad huycpedoxbicy caohnydpitoioxnic ocro nditirtiico noxoidr en i(tNriOc o) x(Fidigeu(rNe O3)9)( F[i2g4u7r]e. (3199)Z[)2-4H7a].lic(1h9oZn)-- dHramlicihdoen, d16ra1 misi da et,ri1s6o1xaiszaolter imsoaxcarzoolildeem fraocmro ltihdee mfroarminteh sepmonagrien cehsopnodnrogseiac hcorntdicraotsei a[2c4o5rt]i.- Icta etexh[2ib45it]s. aItnetixphriobliitfsearanttiivper oalcifteivraittyiv aegaacitnivsti tay vaagraiientyst oaf vcarniceetyr coeflclsa.n Fcoer ecexlalms. pFloer, eitx eaxmhpible-, iitts eaxnhtiibmitestansttaimtice teafsfteactitc oenff ehcutmonanh upmroasntaptero csatantceecra cneclelsr cveilal smvoiadmuloadtiuolna toiofn eopfitehpeiltihael-ltioal-- Molecules 2021, 26, x FOR PEER REVIEW mtoe-smenescehnycmhaylm tarlantrsaitnisointi o[n24[52]4. 5]C. yCtoytotoxtiocx iacctaicvtiitvyi tyofo fcocmompopuonudn d11661314 ooofc c5cc0uu rrss tthrrough Akktt/mmTTOORR ppaaththwwaayy ssuupppprreessssiioonn aannd G22/MM pphhaassee isis bblolocckkeedd vviaia aann iinnccrreeaasseedd eexxprreessssiioonn ooff pp5533 aanndd GADD4455 pprrootteeiinnss ((FFiigguurree 4400)) [[224455]].. O N O N N O O O O O O O OHN O O (19Z)-Halichondramide, 161 Cancer: Lung Cancer: Prostate Cancer Cell: A549 Cancer Cell: PC3 Biological Targets: CDC2,CDC25C, P5, GADD45alpha Biological Targets: PRL3, MMP IC50 = 0.024 μM IC50 = 0.81 μM Figure 40F. iSgtururcet u4r0e. Sotfrtuhcetutrriseo oxfa zthoele tmrisaocrxoalzidoele( 1m9Zac)-rHolaildiceh (o1n9dZr)a-mHiadleicwhoitnhdarasummidmea wryitohf ait ssubimolmogaircya loafc ittisv ibtyi-towards selected coalnocgeircatal ragcettisv.ity towards selected cancer targets. The DichapetalTinhse Dwicehraep eftiarslitn srwepeorertfierdst raesp oar tendoavseal ncolvaeslsc laosfs otrfittreitreprepneoniodids s ffrroomm Dichapetalum Dichapetalum mmadaadgaagsacsacraireinensissi s bbyy AAddddaea-eM-Menesnasha,hA, chAecnhbeancbhaacnhd tahnedir ctoh-ewiro rckoe-rws [o2r4k8e,2rs4 9]. They are [248,249]. They maroes mtlyosftoluyn fdouinndth ien ftahmei lfyamDiilcyh aDpeictahlaapceetaaela(Ccehaaei l(lCethiaaciellaeet)i,acbeuate)r,e bceunt trreecpeonrtt s have con- reports have confifrimrmededt htehierirp rperseesnecnecien inth tehEeu Epuhporhboirabcieaacee,ape,a rptaicrutilcaurllya,rtlhy,e tgheen guesnPuhsy lPlahnytlh-us [250,251]. lanthus [250,251]T.o T-doa-dtea,taeb, oaubtoutwt etwnteyn-stiyx-scioxm cpomoupnodusnbdesl obneglionnggtiongt htios nthoivs enl ocvlaesls colaf stsr itoefr penes have triterpenes have been reported mainly from various species of Dichapetalum and a few from Phyllanthus. They are structural derivatives of dammarane characterized by a unique C-6-C-2-unit connection with a variable C-17 side chain mostly containing spirolactone, lactone, lactol, acetal, methyl ester, or furan moieties. The cytotoxic activity of the dichapetalins was first reported by Achenbach et al. who found that dichapetalin A, 165 exhibited very strong in vitro cytotoxicity about seven times greater than that of podo- phyllotoxin [248]. They also found the compound to inhibit L1210 murine leukemia cells at extremely low doses (EC90 < 0.0001 μg/mL but its sensitivity on human KB carcinoma and murine bone marrow stimulated with GM-CSF was at concentrations four-fold higher [248]. Although the cytotoxicity and cancer cell growth inhibition of the dichapetalins are well known, their biological targets of inhibition are yet to be fully elucidated. An inves- tigation by Long et al. assayed the cytotoxic and anti-proliferative properties of ten dichapetalins against human colorectal carcinoma (HCT116) and human melanoma (WM 266-4) cells and found dichapetalins M, 162 and P, 163 as the most potent, displaying ac- tivities in the10−7 to 10−8 M range [252]. Osei-Safo et al. isolated a novel derivative of dichapetalin P, 164 and two others known dichapetalins X, 165 and A, 166 (Figure 41) from Dichapetalum pallidum and investigated their antiproliferative effects against the human T- lymphocytic leukemia (Jurkat), acute promyelocytic leukemia (HL-60) and T-lympho- blast-like leukemia (CEM) cell lines [253]. All the three isolates were significantly bioac- tive, but dichapetalin X was found to be the most potent against all three cell lines with IC50 of 3.14 μM [253]. Similarly, four new dichapetalins (Pacidusin A, B, C, and D) (Figure 41), 167–170 were recently isolated from young leaves of Phyllanthus acidus and their cy- totoxic activities evaluated [254]. While all the isolated dichapetalins showed moderate activity against BEAS-2B and LO2 normal cell lines with IC50 less than 22.55 μM, they exhibited strong cytotoxic activities against five human cancer cell lines with IC50 ranging between 3.38 and 22.38 μM [254]. Molecules 2021, 26, 7134 34 of 48 been reported mainly from various species of Dichapetalum and a few from Phyllanthus. They are structural derivatives of dammarane characterized by a unique C-6-C-2-unit connection with a variable C-17 side chain mostly containing spirolactone, lactone, lactol, acetal, methyl ester, or furan moieties. The cytotoxic activity of the dichapetalins was first reported by Achenbach et al. who found that dichapetalin A, 165 exhibited very strong in vitro cytotoxicity about seven times greater than that of podophyllotoxin [248]. They also found the compound to inhibit L1210 murine leukemia cells at extremely low doses (EC90 < 0.0001 µg/mL but its sensitivity on human KB carcinoma and murine bone marrow stimulated with GM-CSF was at concentrations four-fold higher [248]. Although the cytotoxicity and cancer cell growth inhibition of the dichapetalins are well known, their biological targets of inhibition are yet to be fully elucidated. An investigation by Long et al. assayed the cytotoxic and anti-proliferative properties of ten dichapetalins against human colorectal carcinoma (HCT116) and human melanoma (WM 266-4) cells and found dichapetalins M, 162 and P, 163 as the most potent, displaying activities in the 10−7 to 10−8 M range [252]. Osei-Safo et al. isolated a novel derivative of dichapetalin P, 164 and two others known dichapetalins X, 165 and A, 166 (Figure 41) from Dichapetalum pallidum and investigated their antiproliferative effects against the human T-lymphocytic leukemia (Jurkat), acute promyelocytic leukemia (HL-60) and T-lymphoblast-like leukemia (CEM) cell lines [253]. All the three isolates were significantly bioactive, but dichapetalin X was found to be the most potent against all three cell lines with IC50 of 3.14 µM [253]. Similarly, four new dichapetalins (Pacidusin A, B, C, and D) (Figure 41), 167–170 were recently isolated from young leaves of Phyllanthus acidus and their cytotoxic activities evaluated [254]. While all the isolated dichapetalins showed moderate activity against BEAS-2B and LO2 normal cell lines with IC50 less than 22.55 µM, they exhibited strongMolecules 2021, 26, x FOR PEER REVIEW 35 of 50 cytotoxic activities against five human cancer cell lines with IC50 ranging between 3.38 and 22.38 µM [254]. FFiigguurree 4411.. SSttrruuccttuurreess ooff tthhee ttrriitteerrppeennooiiddss DiicchhaappeettaalilninssM M, ,P P, X, Xa nanddA A, 7, -7H-HydyrdorxoyxdyidcihcahpaepteatlainlinP, Pa,s aws ewllealls aPsa PciadcuidsiunssinAs- AD-. D. The nutritional benefits of some species belonging to the Kingdom Fungi such as mushroom, Rhizopus, morels, etc. are enormous and are well documented [255]. Recent studies have also found fungi to possess numerous natural products with diverse medic- inal properties for the treatment of infectious and non-infectious diseases [256]. Two po- tent inhibitors of NF-kB function isolated from the fungus family, panepoxydone, 171 and oxasporidion, 172 induced apoptotic proteins and inhibited TNF-α [257,258]. Compound 171 was isolated from Lentinus crinitus (an edible mushroom) while compound 172 was isolated as a mixture of four isomers from fermentations of the ascomycete Chaetomium subspirale (Figure 42) [257,258]. Figure 42. Structures of Panepoxydone and Oxasporidion with a summary of their biological activ- ity towards selected cancer targets. Molecules 2021, 26, x FOR PEER REVIEW 35 of 50 Figure 41. StruMcotulecruelse so2f0 t2h1,e2 t6r,i7te13rp4 enoids Dichapetalins M, P, X and A, 7-Hydroxydichapetalin P, as well as Pacidusins A- 35 of 48 D. The nutritional benefits of some species belonging to the Kingdom Fungi such as mushroom, RhizopuTs,h me onruetlrsit, ieotnca. labree neenfiotrsmoof usos maneds paercei ewseblle ldooncguinmgetnotetdhe [2K5i5n]g. dRoemcenFtu ngi such as studies have alsom fuosuhnrodo fmun, Rgih tiozo ppousss,emsso nreulms, eetrco.uasr eneantuorraml opuros danudctas rwe iwthe ldl idvoecrusme menetdedic-[255]. Recent inal properties fsotru tdhiees threaavtemalesnotf oouf nindfefucntigoiutso apnodss ensosnn-uinmfeercotiuosunsa dtuisraelapseros d[2u5ct6s].w Titwhod ipvoe-rse medicinal tent inhibitors ofp NroFp-ekrBti efusnfocrtiothne itsroelaattmede nfrtoomf i tnhfeec ftuionugsuasn fdamniolny-, ipnafencetpioouxsyddiosneaes, e1s7[12 a5n6]d. Two potent oxasporidion, 17i2npo hinibdituocresdo faNF-κridion, 172pionpdt B uot f cei ucn pcrtiootneiinsos laantedd ifnrohmibittheedf uTnNgus familyd apoptotic proteins and inhiFb-iαte [d2T57N,2 , p58an].e Cpooxmypdoonuen,d1 71 and oxas-F-α [257,258]. Compound 171 171 was isolatedw farsoimso lLaetnedtinfruosm crLiennittiunsu s(acnri neidtuibs l(ea nmeudsibhlreomomus)h wrohomile) wcohmilepcooumnpdo 1u7n2d w17a2s was isolated isolated as a mixatsuarem oixft uforuero fisfoomureirsso mfroerms ffreormmefenrtmateinotnast ioofn sthoef tahsecoamscyomceytec eCtehaCehtaoemtoiummiu m subspirale subspirale (Figure(F 4ig2u) r[e25472,)2[5285]7. ,258]. Molecules 2021, 26, x FOR PEER REVIEW 36 of 50 Figure 42F.iSgtururec t4u2r.e Sstoruf cPtaunreps ooxfy PdaonneepaonxdydOoxnaes paonrdid Oioxnaswpiothridaisounm wmitahr ya osuf mthmeirarbyio olof gthiceailr abcitoivloitgyictaolw aacrtdivs-selected cancer taritgye ttso.wards selected cancer targets. Candidaspongiolide, 173 is a polyketide extracted from Candidaspongia sp [259]. It in- hibits protein syntCheasnids idanasdp oinndguiocleids ea,p1o73ptiossaisp ionly bkoetthid Ue e2x5t1r aacntedd HfrComT1C1a6n cdeidllass,p tohneg ilaasttpe[r2 59]. It in part by a cainshpiabsites 1p2ro—tedinepsyenntdheensits panadthiwndauyc e[2s5a9p]o. pItno saisdidnitbiootnh, Uco25m1paonudnHdC 1T7131 6incehlilbs,itths e latter in part by a caspase 12—dependent pathway [259]. In addition, compound 173 inhibits proliferation o p fr houlifmeraanti omneolfanhuommaan cmelelsla inno am saecleeclltsivine amsaenlencteirv ecommanpnaerredco tmo pbarreeadstt oanbrde alustnagn d lung cancer cell linecsa n(Fceigr ucerlel l4in3)e s[2(F6i0g]u. re 43) [260]. Figure 43. FSitgrucrteu 4re3.o Sfttrhuectpuorley koeft tidhe Cpoanlydkidetaisdpeo Cngainodliiddeawspitohnagisoulimdme wariytho fa istsumbiomloagriyc aolf aictsti vbitoylotogwicarld asctsievleitcyte d cancer targteotsw. ards selected cancer targets. Ophiobolin OO, 1p7h4io ibs oal ifnunOg, a1l7 m4 iestaabfoulnitgea. lItm ise taa bsoeslitteer.teIpt eisnoaisde sbteelrotenpgeinnogi dtob tehloen ogpinhg- to the iobolane groupop ohfi toebropleanneoigdrso uispoloaftteedr pfreonmoid Assipseorlgaitleldusf ruosmtuAs [s2p6er1g]i.l lIut sisu sat upso[t2e6n1t] .anIttiis-taumpooter nt anti- drug for human breast cancer [262]. It induces G1 phase arrest in human breast cancer when tested on the Michigan cancer foundation (MCF)-7 cells and reduces the phosphor- ylation level of protein kinase B (AKT) and Glycogen synthase kinase-3β (GSK3β). It also induces down-regulation of cyclin D1 [262]. Incubation of 174 with glioblastoma cancer cells resulted in the induction of the death of the glioblastoma cells as a result of G0/G1 cell cycle arrest and Ca2+-activated K+ channel (BKCa) ion channel activity inhibition (Fig- ure 44) [261,262]. Penicitrinine A, 175 is an alkaloid with a unique spiro skeleton, isolated from a ma- rine-derived fungus Penicillium citrinum. It showed toxicity against cellosaurus cell line A- 375, human cell lines SPC-A1 and HGC-27, and human cancer cell lines with IC50 values of 20.1, 28.6 and 29.4 μM, respectively [263]. The anti-metastatic activity is purported to be by decreasing the expression of Bcl-2 and increasing the expression of Bax [263]. Fur- thermore, compound 175 suppresses metastatic activity of A-375 cells by regulating the expression of matrix metallopeptidase 9 (MMP-9) and its specific tissue inhibitor of met- alloproteinase 1 (TIMP-1) (Figure 44) [263]. Salinomycin, 176 is a monocarboxylic polyether antibiotic isolated from Streptomyces albus strain (Figure 45) [264,265]. Although the exact mechanism of its anticancer action is unknown, 176 is suspected to decrease the expression of adenosine triphosphate-binding cassette transporter and interfere with the protein kinase B (Akt) signaling pathway [264]. Salinomycin suppresses the phosphorylation of low-density lipoprotein receptor-related protein 6 (LRP6) and the expression of β-catenin and glycogen synthase kinase-3β (p-GSK- 3β). Additionally, it induces the production of ROS and mitochondrial membrane depo- larization resulting in the activation of caspase 3. It also causes the induction of poly(ADP- ribose) polymerase-1 (PARP-1) cleavage, and the elicitation of DNA damage [264]. Con- sequently, induction of tumor cell death results leading to inhibition of cancer cell growth. The compound also induces autophagic cell death, inhibits the NF-KB pathway and acti- vates p38 mitogen-activated protein kinase (MARK) pathway [266]. Molecules 2021, 26, 7134 36 of 48 tumor drug for human breast cancer [262]. It induces G1 phase arrest in human breast cancer when tested on the Michigan cancer foundation (MCF)-7 cells and reduces the phosphorylation level of protein kinase B (AKT) and Glycogen synthase kinase-3β (GSK3β). It also induces down-regulation of cyclin D1 [262]. Incubation of 174 with glioblastoma Molecules 2021, 26, x FOR PEER REVIEW cancer cells resulted in the induction of the death of the glioblastoma ce3l7l sofa 5s0a result of G0/G1 cell cycle arrest and Ca2+-activated K+ channel (BKCa) ion channel activity inhibition (Figure 44) [261,262]. Figure 44F.igSutrruec t4u4r.e Sstoruf cthtuerseess toefr ttehpee nseosidteOrtpephieonbooildin Oapndhitohbeoslpinir oanadlk tahloei dspPireon iaciltkrainloinide APewniitchitrainsuinmem Aa rwyiothf tah eir biologicasluamctimviatyryto owf atrhdesirs ebleioctleodgiccaanlc aercttiavrigteyt st.owards selected cancer targets. Penicitrinine A, 175 is an alkaloid with a unique spiro skeleton, isolated from a marine- derived fungus Penicillium citrinum. It showed toxicity against cellosaurus cell line A-375, human cell lines SPC-A1 and HGC-27, and human cancer cell lines with IC50 values of 20.1, 28.6 and 29.4 µM, respectively [263]. The anti-metastatic activity is purported to be by decreasing the expression of Bcl-2 and increasing the expression of Bax [263]. Furthermore, compound 175 suppresses metastatic activity of A-375 cells by regulating the expression of matrix metallopeptidase 9 (MMP-9) and its specific tissue inhibitor of metalloproteinase 1 (TIMP-1) (Figure 44) [263]. Salinomycin, 176 is a monocarboxylic polyether antibiotic isolated from Streptomyces albus strain (Figure 45) [264,265]. Although the exact mechanism of its anticancer action is un- known, 176 is suspected to decrease the expression of adenosine triphosphate-binding cas- sette transporter and interfere with the protein kinase B (Akt) signaling pathway [264]. Sali- nomycin suppresses the phosphorylation of low-density lipoprotein receptor-related pro- tein 6 (LRP6) and the expression of β-catenin and glycogen synthase kinase-3β (p-GSK-3β). Additionally, it induces the production of ROS and mitochondrial membrane depolariza- tion resulting in the activation of caspase 3. It also causes the induction of poly(ADP-ribose) Figure 45. Structures of the monocarboxylic poollyemtheerar sSea-l1in(PoAmRyPci-n1 )acnldea tvhaeg ne,uacnledosthideee alinctiitmateiotanboofliDteN CAorddaymceapgien[ w26i4th]. aC onsequently, summary of their biological activity towards isnedleucctteido ncaonfcetur mtaorgrectes.l l death results leading to inhibition of cancer cell growth. The compound also induces autophagic cell death, inhibits the NF-κB pathway and activates Cordycepinp,3 187m7,i tao gneunc-laecotisviadtee danptriomteeintakbionlaistee (fMroAmR CKo)rpdaytchewpsa ym[i2li6t6a]r.is [267] is an aden- osine analogue which is readily phosphorylated to its mono-, di- and tri-phosphate deriv- atives intracellularly [268]. Compound 177 kills cancer cells resistant to pro-apoptotic stimuli, induces non-apoptotic-related death pathways in cancer cells, and impairs the biology of cancer stem cells (CSCs) [269]. It also causes cell cycle arrest but in the G2/M phase by regulating c-Jun N-terminal kinase activation and TNFα-induced NF-kB activa- tion [267,268]. Other oxygen heterocyclic compounds which have been screened for multi-target an- ticancer properties are the oxindole-benzofuran hybrids. Compounds 178–180 were found to possess activity against breast cancer when tested against CDK2/GSK-3β. They were found to be more potent in comparison with staurosporine, 181, a cell permeable alkaloid isolated from Streptomyces staurosporeus [270]. The IC50 values against MCF-7 cell lines were 3.41 μM (178), 3.45 μM (179), 2.27 μM (180), and 4.81 μM (179). When tested against breast cancer cell line T-47D, activities of 3.82, 4.53 and 7.80 μM, for compounds 178, 179 and 180, respectively were obtained while that of 181 was 4.34 μM. Compounds 179 and Molecules 2021, 26, x FOR PEER REVIEW 37 of 50 Molecules 2021, 26, 7134 37 of 48 Figure 44. Structures of the sestertepenoid Ophiobolin and the spiro alkaloid Penicitrinine A with a summary of their biological activity towards selected cancer targets. FiguFrieg u4r5e. 4S5tr. uSctrtucrteusr eosf othf eth me monooncoacrabrobxoyxylilci cppoolylyeetthheerr Salinomyciin aannddt htheen nuuclceloesoidsiedaen atinmtiemtaebtoalbitoeliCteo rCdoyrcdepyicnepwinit hwaith a sumsmumarmy aorfy tohfetihr ebirioblioogloicgaicl alcaticvtiivtyit ytotwowaardrdss sseelleecctted cancerr ttaarrggeetsts. . CoCrodrydcyecpepinin, 1, 7177,7 a, naunculecolesoidsied aenatnimtimeteatbaobloitliet efrofrmom CoCrodrydcyecpesp ms miliitlaitrairsi [s2[6276]7 i]s iasna anden- osaindee naonsailnoegaunea wloghuicehw ish ricehadisilrye apdhiolyspphhoorsyplhaotreydl attoe ditst omitosnmo-o,n doi--, adni-da tnrdi-ptrhi-opshpohsapthea dteeriv- atidveersiv iantitvreasceinllturalacerlllyu l[a2r6ly8][.2 6C8o].mCpomoupnodu n1d7177 7kikllisll sccaanncceerr cceellllssr erseissitsatnatntto tpor op-arpoo-apptootpictotic stistimuli, induces non-apoptotibmioulolig, yinodfucacnesc enrosnte-mapcoeplltso(tCic c--rreellaatteedd ddeeaatthhp paaththwwayasysin inca cnacnercecre lcls, and impairs theSCs) [269]. It also causes cell cycle arreset lblsu,t ainndth iemGp2a/iMrs the bioplhoagsye boyf rceagnucleart isntgemc-J ucenllNs -(tCerSmCisn)a [l2k6in9]a.s eIt aacltsivoa ctiaounseans dceTlNl cFyαc-lien daurrceesdt NbuFt- κiBn atchteiv Ga-2/M phtaiosne [b2y6 7r,e2g6u8]l.ating c-Jun N-terminal kinase activation and TNFα-induced NF-kB activa- tion [26O7t,h2e6r8]o.x ygen heterocyclic compounds which have been screened for multi-target antOictahnecre roxpyrogpeenr htietsearroecythcelico cxoinmdpoloeu-bnednsz wofhuircahn hhayvber ibdese. nC socmrepeonuendd fsor1 7m8u–1lt8i0-tawregreet an- ticfaonucnedr tporopposesretsiessa acrtiev tithyea ogxaiindstoblere-baestnczaonfcuerrawn heynbrteidstse.d CaogmaipnostuCnDdsK 127/8G–S1K80-3 wβ.eTreh efoyund tow peorsesfeosus nadcttiovibtye magoarienpsto tbernetaisnt coamncpearr iwsohnenw ittehstsetdau argosapinosrti nCe,D1K812,/Ga SceKl-l3pβe.r mTheeayb lewere Molecules 2021, 26, x FOR PEER REfoVuaIElnkWda l otoid bies omlaoterde pfrootmenStt irnep ctoomypceasrsitsaounr owspiotrhe ussta[u27r0o]s.pTohreinICe,5 10 8v1a,l uae cseallg paienrsmt MeaCbFle-7 aclkelallo3id8 of 50 isolilnaetesdw ferroem3. 4S1trµeMpto(m17y8c)e,s3 .s4t5auµrMosp(o1r7e9u),s 2[.22770µ]M. T(h1e8 0I)C, a50n dva4l.u8e1sµ aMga(i1n7s9t) .MWChFe-n7 tceestlel dlines weargea i3n.4st1b μreMas (t1c7a8n)c, e3r.4c5e lμl lMin e(1T7-94)7,D 2,.2a7c tμivMiti (e1s8o0f),3 .a8n2d, 4 4.5.831a μnMd 7 (.18079µ)M. W, fhoernco tmespteodu nadgsainst br1e71a 8, 8s0t 1c7a9nacnedr c1e8l0l, lriensep Tec-t4i7vDel,y awcteirveitoiebsta oinf e3d.8w2,h 4il.e53th aantdo f 181 was 4.34µM. Compounds 179 a nwde1re80 found to inhibit CDK 7.80 μM, for compounds 178, 179 and 180, were found to inhibit C 2D/KG2S/KG-S3Kβ -r3eβsurelstuinltgin igni nceclell lccyyccllee aarrrreesstt iinnt htheeG G2/2M/M phase p(hFaigseu(rFerie g4su6pr)e e[c24t7i6v0)e][l.2 y7 0w].ere obtained while that of 181 was 4.34 μM. Compounds 179 and FFigiguurere4 64.6S. tSrturcutuctruesreosf ofx ionxdionlde-oblen-bzoefnuzroanfuhryabnr ihdysb1r6i2d–s1 16642a–n1d64th aenbdis t-hined boilse-Sintaduorloes pSotariunreowspitohrine with aas suummmmarayryo fotfh tehirebiri obloiogliocgalicaaclt iavcittyivtiotwy atordwsasredlesc tseedleccatnecde rcatanrcgert st.argets. 3. Conclusions Chemotherapy is among the various strategies available for cancer treatment. How- ever, many of the available chemotherapeutic agents suffer serious drawbacks including drug inefficiencies, resistance, and diverse and intertwining pathways of the pathogenesis of cancer diseases. Multi-target drugs have been proposed as the effective means of treat- ing cancers. In this review, different classes of synthetic, semisynthetic, and naturally oc- curring heterocyclic compounds with multi-targeting properties have been evaluated as potential chemotherapeutic agents for various forms of cancer. The classes of heterocyclics considered in this review are the nitrogen, sulfur, oxygen, combined nitrogen/sulfur, and nitrogen/oxygen heterocyclics. The mode of action of these compounds includes inhibi- tion of cell growth, induction of apoptosis and reduction of cell metastasis via downreg- ulation of topoisomerase I and II, G2/M and G0/G1 cell cycle arrest, HDAC, tubulin polymerization, VEGFR, and EGFR. Some of the heterocyclic compounds also suppress NF-κB, STAT3, P13K/AKT, BRAF, and MDR. Author Contributions: Conceptualization of the project: I.A.-M., R.K.A., D.O.-S. and P.O.S.; Re- search and collection of material for the project: P.O.S., R.K.A., I.A.-M. and D.O.-S.; Drafting of the manuscript: P.O.S., R.K.A., I.A.-M. and D.O.-S.; Comprehensive editing and finalization of the man- uscript: I.A.-M., R.K.A., P.O.S. and D.O.-S. All authors have read and agreed to the published ver- sion of the manuscript. Funding: This research received no external funding. Acknowledgments: We acknowledge with thanks and appreciation the award of a postgraduate scholarship to Patrick Opare Sakyi by the Ghana National Petroleum Corporation (GNPC). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability: Not applicable. Conflicts of Interest: The authors have no issues of conflict of interest regarding to the manuscript and its contents. References 1. Dhiman, N.; Kaur, K.; Jaitak, V. Tetrazoles as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies. Bioorg. Med. Chem. 2020, 28, 115599. https://doi.org/10.1016/j.bmc.2020.115599. 2. Abbot, V.; Sharma, P.; Dhiman, S.; Noolvi, M.N.; Patel, H.M.; Bhardwaj, V. Small hybrid heteroaromatics: Resourceful biological tools in cancer research. RSC Adv. 2017, 7, 28313–28349. https://doi.org/10.1039/c6ra24662a. Molecules 2021, 26, 7134 38 of 48 3. Conclusions Chemotherapy is among the various strategies available for cancer treatment. How- ever, many of the available chemotherapeutic agents suffer serious drawbacks including drug inefficiencies, resistance, and diverse and intertwining pathways of the pathogene- sis of cancer diseases. Multi-target drugs have been proposed as the effective means of treating cancers. In this review, different classes of synthetic, semisynthetic, and naturally occurring heterocyclic compounds with multi-targeting properties have been evaluated as potential chemotherapeutic agents for various forms of cancer. The classes of heterocyclics considered in this review are the nitrogen, sulfur, oxygen, combined nitrogen/sulfur, and nitrogen/oxygen heterocyclics. The mode of action of these compounds includes inhibition of cell growth, induction of apoptosis and reduction of cell metastasis via downregulation of topoisomerase I and II, G2/M and G0/G1 cell cycle arrest, HDAC, tubulin polymeriza- tion, VEGFR, and EGFR. Some of the heterocyclic compounds also suppress NF-κB, STAT3, P13K/AKT, BRAF, and MDR. Author Contributions: Conceptualization of the project: I.A.-M., R.K.A., D.O.-S. and P.O.S.; Re- search and collection of material for the project: P.O.S., R.K.A., I.A.-M. and D.O.-S.; Drafting of the manuscript: P.O.S., R.K.A., I.A.-M. and D.O.-S.; Comprehensive editing and finalization of the manuscript: I.A.-M., R.K.A., P.O.S. and D.O.-S. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. 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