2. Academic Validation
  3. Design, synthesis and biological activity of N5-substituted tetrahydropteroate analogs as non-classical antifolates against cobalamin-dependent methionine synthase and potential anticancer agents

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.
Meng Wang 1,  Chao Tian 2,  Liangmin Xue 2,  Hao Li 2,  Jing Cong 2,  Fang Fang 2,  Jiajia Yang 2,  Mengmeng Yuan 2,  Ying Chen 2,  Ying Guo 2,  Xiaowei Wang 2,  Junyi Liu 3,  Zhili Zhang 4
Affiliations

Affiliations

  • 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: jyliu@bjmu.edu.cn.
  • 4 Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: lilybmu@bjmu.edu.cn.
PMID: 32058237 DOI: 10.1016/j.ejmech.2020.112113
Abstract

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.

Keywords

Anticancer; Antifolate; Inhibitor; Methionine synthase; Pyrido[3,2-d]pyrimidine.

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