新型二氢叶酸还原酶抑制剂的合成及生物活性测试

引用本文: 张袁魁, 陈简, 詹晓平, 徐赟, 刘增路, 毛振民. 新型二氢叶酸还原酶抑制剂的合成及生物活性测试[J]. 有机化学, 2016, 36(3): 664-669. doi: 10.6023/cjoc201509042 shu

Citation: Zhang Yuankui, Chen Jian, Zhan Xiaoping, Xu Yun, Liu Zenglu, Mao Zhenmin. Synthesis and Bioactivity of Novel Dihydrofolate Reductase Inhibitor[J]. Chinese Journal of Organic Chemistry, 2016, 36(3): 664-669. doi: 10.6023/cjoc201509042 shu

新型二氢叶酸还原酶抑制剂的合成及生物活性测试

1.
上海交通大学药学院上海 200240

通讯作者: 毛振民

基金项目:
国家科技重大新药创制专项(No. 2010ZX09401-404)资助项目. (No. 2010ZX09401-404)

摘要: 以氯乙腈和2-噻吩甲醛为原料, 通过接合经缩合、环合、还原、硝化等步骤合成的两个关键中间体1c和2d, 设计合成了两个新型二氢叶酸还原酶抑制剂的衍生物3c和4b, 其结构经¹H NMR、¹³C NMR和MS方法验证. 采用噻唑蓝法对目标化合物进行了抗肿瘤活性测试, 结果表明3c对筛选的5种肿瘤细胞株的抑制活性均比阳性对照药洛美曲索、甲氨蝶呤和培美曲塞强, 4b对Hep-G2的抑制活性比阳性对照药洛美曲索、甲氨蝶呤和培美曲塞强, 而且3c和4b对正常细胞株——人脐带内皮血管平滑肌细胞的抑制活性明显比甲氨蝶呤和培美曲塞弱.

关键词:

English

Synthesis and Bioactivity of Novel Dihydrofolate Reductase Inhibitor

1.
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240

Corresponding author: 毛振民

Received Date: 29 September 2015
Available Online: 06 November 2015
Fund Project:
国家科技重大新药创制专项(No. 2010ZX09401-404)资助项目.

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:

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1.
沈阳化工大学材料科学与工程学院沈阳 110142

新型二氢叶酸还原酶抑制剂的合成及生物活性测试

通讯作者: 毛振民

English

Synthesis and Bioactivity of Novel Dihydrofolate Reductase Inhibitor

Corresponding author: 毛振民

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通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

新型二氢叶酸还原酶抑制剂的合成及生物活性测试

通讯作者: 毛振民

English

Synthesis and Bioactivity of Novel Dihydrofolate Reductase Inhibitor

Corresponding author: 毛振民

CCS Chemistry：嵌段共聚物自组装成 “三明治”二维有机材料，实现纳米级压力传感功能

CCS Chemistry：颜徐州、鲍哲南： 你的皮肤可能是一片SPMs

CCS Chemistry：工作高效不疲劳，只须让催化剂动起来

CCS Chemistry：静电组装导向聚合- 聚电解质纳米凝胶量化制备新策略

CCS Chemistry：金黄色葡萄球菌醛基脱氢酶是如何识别特异性底物的？

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