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

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 44卷 / 02期

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

页码：764 / 771

页数：8

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