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

Meng Wang; Chao Tian; Liangmin Xue; Hao Li; Jing Cong; Fang Fang; Jiajia Yang; Mengmeng Yuan; Ying Chen; Ying Guo; Xiaowei Wang; Junyi Liu; Zhili Zhang

doi:10.1016/j.ejmech.2020.112113

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. Epub 2020 Feb 5.

Authors

Meng Wang¹, Chao Tian², Liangmin Xue², Hao Li², Jing Cong², Fang Fang², Jiajia Yang², Mengmeng Yuan², Ying Chen², Ying Guo², Xiaowei Wang², Junyi Liu³, Zhili Zhang⁴

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.

MeSH terms

5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / antagonists & inhibitors*
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / chemistry
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Catalytic Domain
Cell Line, Tumor
Drug Design
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Folic Acid Antagonists / chemical synthesis
Folic Acid Antagonists / metabolism
Folic Acid Antagonists / pharmacology*
G1 Phase Cell Cycle Checkpoints / drug effects
Humans
Molecular Docking Simulation
Molecular Structure
Protein Binding
Pterins / chemical synthesis
Pterins / metabolism
Pterins / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Pterins
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
MTR protein, human