Molecular modeling studies and synthesis of novel quinoxaline derivatives with potential anti-cancer activity as inhibitors of methionine synthase

摘要

Methionine synthase (MetS) catalyses the transfer of a methyl group from the methyltetrahydrofolate (MTHF) to homocysteine to produce methionine and tetra-hydrofolate. MetS is over-expressed in the cytosol of certain breast and prostate tumor cells. In this article, we designed, synthesized, and evaluated the biological activity of a series of substituted quinoxaline derivatives that mimic the MTHF in the structure. The main aim was to develop inhibitors that zcould inhibit the enzyme reaction by blocking the binding of MTHF. These inhibitors were docked into the MTHF binding domain in such the same way as MTHF in its binding domain. Compound 4-({(6-nitro-quinoxalin-2-yl)methylamino}methyl)benzoic acid showed the lowest free energy of the binding (- 152.62 kJ/mol) and showed the lowest IC_(50) values of 45 +- 9 and 53 +- 9 uM against two types of cancer cell lines PC-3 and MCF-7, respectively.