Synthesis and Bioactivity of Novel Dihydrofolate Reductase Inhibitor

doi:10.6023/cjoc201509042

Chin. J. Org. Chem. ›› 2016, Vol. 36 ›› Issue (3): 664-669.DOI: 10.6023/cjoc201509042 Previous Articles Next Articles

Notes

新型二氢叶酸还原酶抑制剂的合成及生物活性测试

张袁魁, 陈简, 詹晓平, 徐赟, 刘增路, 毛振民

上海交通大学药学院上海 200240

收稿日期:2015-09-29 修回日期:2015-10-30 发布日期:2015-11-06
通讯作者: 毛振民 E-mail:zmmao@sjtu.edu.cn
基金资助:
国家科技重大新药创制专项(No. 2010ZX09401-404)资助项目.

Synthesis and Bioactivity of Novel Dihydrofolate Reductase Inhibitor

Zhang Yuankui, Chen Jian, Zhan Xiaoping, Xu Yun, Liu Zenglu, Mao Zhenmin

School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240

Received:2015-09-29 Revised:2015-10-30 Published:2015-11-06
Supported by:
Project supported by the National Significant and Special Project of New Created Drugs (No. 2010ZX09401-404).

1. Synthesis and Bioactivity of Novel Dihydrofolate Reductase Inhibitor.PDF(611KB)

Abstract

In order to obtain antitumor candidates with potent activity, two novel analogues of dihydrofolate reductase (DHFR) inhibitors 3c and 4b were designed and synthesized. The synthetic routes were as follows: 1c was synthesized using chloroacetonitrile, carboxylate and 2,4,6-triamino-pyrimidine as raw materials by condensation, cyclization and reduction. 2d was synthesized using 2-thiophene formaldehyde and glutamate as raw materials by nitrification, oxidation, condensation and reduction. Then target product 3c was synthesized using 1c and 2d as raw materials by reductive amination and hydrolysis. Target product 4b was synthesized using 1c and 2d as raw materials by 2 steps of reductive amination and hydrolysis. The structures of target products were confirmed by the way of ¹H NMR, ¹³C NMR and MS. The in vitro antitumor activities of target products were evaluated by MTT method. The results showed that 3c exhibited stronger antitumor activity against screened five tumor cell lines (CCRF-CEM, L1210, A549, SGC-7901 and Hep-G2) than the positive control lometrexol, methotrexate and pemetrexed. 3c exhibited stronger antitumor activity against Hep-G2 than the positive control lometrexol, methotrexate and pemetrexed. In addition, 3c and 4b showed much weaker antiproliferative activity toward normal cell SMC than the positive control methotrexate and pemetrexed. This research could provide a theoretical basis for the development of new antitumor drugs.

Key words: DHFR inhibitor, antitumor bioactivity, synthesis

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Zhang Yuankui, Chen Jian, Zhan Xiaoping, Xu Yun, Liu Zenglu, Mao Zhenmin. Synthesis and Bioactivity of Novel Dihydrofolate Reductase Inhibitor[J]. Chin. J. Org. Chem., 2016, 36(3): 664-669.

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新型二氢叶酸还原酶抑制剂的合成及生物活性测试

Synthesis and Bioactivity of Novel Dihydrofolate Reductase Inhibitor

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