Synthesis and Biological Properties of Ferrocenyl and Organic Methotrexate Derivatives
No Thumbnail Available
Date
2024
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ACS Omega
Abstract
Synthesis and biological activity of two series of modified side chain methotrexate (MTX) derivatives are presented,
one with a ferrocenyl moiety inserted between the pteroyl and glutamate portions of the molecule and the other with glutamate
substituted for short chain amino acids. Ferrocenyl derivatives of MTX turned out to be rather moderate inhibitors of dihydrofolate
reductase (DHFR) although molecular modeling suggested more effective interactions between these compounds and the target
enzyme. More interestingly, ferrocene-decorated MTX derivatives were able to impede the proliferation of four murine and human
cell lines as well as their methotrexate-resistant counterparts, overcoming the multidrug resistance (MDR) barrier. They were also
able to directly interact with Abcc1, an MDR protein. Of the amino acid pteroyl conjugates, the γ-aminobutyric acid derivative was
an efficient inhibitor of DHFR but had no effect on cell proliferation in the concentration range studied while a taurine conjugate
was a poor DHFR inhibitor but able to affect cell viability. We postulate that modification of the methotrexate side chain may be an
efficient strategy to overcome efflux-dependent methotrexate resistance.
Description
Research Article
Keywords
Synthesis, Biological Properties, Ferrocenyl, Methotrexate