Novel 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives as dihydrofolate inhibitor: Design, synthesis and antifolate activity

被引:18
作者
Zhang, Zhili [1 ]
Wu, Jun [2 ]
Ran, Fuxiang [2 ]
Guo, Ying [1 ]
Tian, Ran [2 ]
Zhou, Shouxin [1 ]
Wang, Xiaowei [1 ]
Liu, Zhenming [2 ]
Zhang, Liangren [2 ]
Cui, Jingrong [2 ]
Liu, Junyi [1 ]
机构
[1] Peking Univ, Dept Biol Chem, Sch Pharmaceut Sci, Beijing 100083, Peoples R China
[2] Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100083, Peoples R China
关键词
Catalytic reduction; Potential antitumor agents; Folate derivatives; Molecular modeling; 5,10-DIDEAZA-5,6,7,8-TETRAHYDROFOLIC ACID DDATHF; COLLAGEN-INDUCED ARTHRITIS; BIOLOGICAL EVALUATION; THYMIDYLATE SYNTHASE; ANTITUMOR AGENTS; FOLIC-ACID; RHEUMATOID-ARTHRITIS; 8-DEAZAFOLIC ACID; ANALOGS; METHOTREXATE;
D O I
10.1016/j.ejmech.2008.04.017
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
We report, for the first time, the synthesis and biological activities of 8-deaza-5,6,7,8-tetrahydroaminopterin 9, and the 5-substituted and 5,10-disubstituted analogues 11, 13, 15, and 17. The analogues were obtained from key compound diethyl 8-deaza-5,6,7,8-tetrahydroaminopterin 8 following the catalytic reduction of the pyridine ring of diethyl 8-deaza aminopterin 5. The five novel 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives were assayed in vitro for their cytotoxicity on BGC-823, HL-60, Bel-7402 and Hela tumor cell lines, and inhibition on recombinant human dihydrofolate reductase (DHFR), among which the most potent molecule (compound 9) was about 4- to 10-fold poorer than MTX on the four kinds of tumor cell lines, and its effect on DHFR was about 17-fold poorer than MTX. The docking studies were followed to explain the biological testing results. (c) 2008 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:764 / 771
页数:8
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