具噻吩环8-去氮杂叶酸类似物的合成及生物活性研究
收稿日期: 2012-03-12
修回日期: 2012-05-11
网络出版日期: 2012-06-04
基金资助
国家自然科学基金(Nos. 21042009, 21172014)和国家科技部(No. 2009ZX09301-010)资助项目.
Synthesis and Bioactivity of 8-Deaza Folic Acid Analogues of Thiophene
Received date: 2012-03-12
Revised date: 2012-05-11
Online published: 2012-06-04
Supported by
Project supported by the National Science Foundation of China (Nos. 21042009, 21172014) and the Ministry of Science and Technology of China (No. 2009ZX09301-010).
根据叶酸代谢中蛋氨酸合成酶的作用机理和二氢叶酸还原酶抑制剂的结构特点, 设计噻吩取代苯环的8-去氮杂叶酸类似物作为双靶点抑制剂. 以噻吩-2-甲酸为原料, 与谷氨酸二乙酯连接后经过硝化、还原、缩合、水解, 得到两个目标化合物, 经1H NMR, 13C NMR和MS对化合物的结构进行了表征. 初步生物活性结果表明, 此类化合物对两种酶都有一定的抑制作用, 其中一个化合物对蛋氨酸合成酶的抑制IC50为25.2 μmol/L, 对二氢叶酸还原酶的抑制IC50为2.3 μmol/L.
关键词： 具噻吩8-去氮杂叶酸类似物; 蛋氨酸合成酶; 二氢叶酸还原酶; 硝化; 生物活性
周受辛 , 田超 , 郭莹 , 王孝伟 , 刘俊义 , 张志丽 . 具噻吩环8-去氮杂叶酸类似物的合成及生物活性研究[J]. 有机化学, 2012 , 32(10) : 1944 -1950 . DOI: 10.6023/cjoc1203122
Based on the action mechanism of methionine synthase and structures of inhibitors against dihydrofolic reductase, thiophene derivatives of 8-deaza folic acid were designed as dual-target inhibitors. Two target compounds were obtained by nitration, reduction, condensation, and hydrolysis with 2-thiophenecarboxylic acid as starting material, and were characterized by 1H NMR, 13C NMR and MS techniques. The inhibitory activities against methionine synthase and recombinant human dihydrofolate reductase were determined. The target compounds showed inhibitory activity on both two enzymes. The IC50s of one compound were 25.2 and 2.3 μmol/L against methionine synthase and recombinant human dihydrofolate reductase, respectively.
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