title: 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.
authors.affiliation: Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Zhang
authors.forename: Chao
authors.initials: C
authors.lastname: Tian
authors.forename: Shouxin
authors.initials: S
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.forename: Jie
authors.initials: J
authors.lastname: Xia
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Liu
authors.forename: Biao
authors.initials: B
authors.lastname: Wang
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griff
authors.forename: Yansheng
authors.initials: Y
authors.lastname: Du
authors.forename: Junyi
authors.initials: J
authors.lastname: Liu
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013763:Tetrahydrofolates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D013763:Tetrahydrofolates; C030371:5,6,7,8-tetrahydrofolic acid; D013762:Tetrahydrofolate Dehydrogenase; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase