Mechanism-based design, synthesis and biological studies of N5-substituted tetrahydrofolate analogs as inhibitors of cobalamin-dependent methionine synthase and potential anticancer agents

A number of 8-deazatetrahydrofolates bearing electrophilic groups on N5 were designed and synthesized based on the action mechanism of methionine synthase, and their biological activities were investigated as well. Compounds (11b, 12b and 16) showed the most active against methionine synthase (IC50: 8.11 μM, 1.73 μM, 1.43 μM). In addition, the cytotoxicity to human tumor cell lines and dihydrofolate reductase (DHFR) inhibition by target compounds were evaluated.

Graphical abstractA number of 8-deazatetrahydrofolates bearing electron-deficient groups on N5 were designed and synthesized based on the action mechanism of methionine synthase, and their biological activities were investigated as well.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We designed the inhibitors basing on the mechanism of methionine synthase. ► A number of 8-deazatetrahydrofolates bearing electron-deficient groups on N5 were synthesized. ► Target compounds and key intermediates were evaluated against MetS and tumor cell lines.