Design, synthesis and biological activity of N5-substituted tetrahydropteroate analogs as non-classical antifolates against cobalamin-dependent methionine synthase and potential anticancer agents
- Eur J Med Chem. 2020 Mar 15:190:112113. doi: 10.1016/j.ejmech.2020.112113.
- 1. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China; College of Pharmacy, Beihua University, Jilin, 132013, China.
- 2. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
- 3. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China. Electronic address: [email protected].
- 4. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: [email protected].
Cobalamin-dependent methionine synthase (MetH) is involved in the process of tumor cell growth and survival. In this study, a novel series of N5-electrophilic substituted tetrahydropteroate analogs without glutamate residue were designed as non-classical antifolates and evaluated for their inhibitory activities against MetH. In addition, the cytotoxicity of target compounds was evaluated in human tumor cell lines. With N5-chloracetyl as the optimum group, further structure research on the benzene substituent and on the 2,4-diamino group was also performed. Compound 6c, with IC50 value of 12.1 μM against MetH and 0.16-6.12 μM against five Cancer cells, acted as competitive inhibitor of MetH. Flow cytometry studies indicated that compound 6c arrested HL-60 cells in the G1-phase and then inducted late Apoptosis. The molecular docking further explained the structure-activity relationship.