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

Zhili Zhang; Chao Tian; Shouxin Zhou; Wei Wang; Ying Guo; Jie Xia; Zhenming Liu; Biao Wang; Xiaowei Wang; Bernard T Golding; Roger J Griff; Yansheng Du; Junyi Liu

doi:10.1016/j.ejmech.2012.09.027

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

Eur J Med Chem. 2012 Dec:58:228-36. doi: 10.1016/j.ejmech.2012.09.027. Epub 2012 Oct 9.

Authors

Zhili Zhang¹, Chao Tian, Shouxin Zhou, Wei Wang, Ying Guo, Jie Xia, Zhenming Liu, Biao Wang, Xiaowei Wang, Bernard T Golding, Roger J Griff, Yansheng Du, Junyi Liu

Affiliation

¹ Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.

PMID: 23124219
DOI: 10.1016/j.ejmech.2012.09.027

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / antagonists & inhibitors*
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Death / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HeLa Cells
Humans
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Tetrahydrofolate Dehydrogenase / metabolism
Tetrahydrofolates / chemical synthesis
Tetrahydrofolates / chemistry
Tetrahydrofolates / pharmacology*

Substances

Antineoplastic Agents
Enzyme Inhibitors
Tetrahydrofolates
5,6,7,8-tetrahydrofolic acid
Tetrahydrofolate Dehydrogenase
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase