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

Abstract A number of 8-deazatetrahydrofolates bearing electrophilic groups on N 5 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 (IC 50 : 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.