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有机化学
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有机化学 ›› 2011, Vol. 31 ›› Issue (11): 1820-1827. 上一篇    下一篇

研究论文

4-氨基-N8,N10-二碳杂-N5-取代四氢叶酸类似物的合成及生物活性研究

田超，李超，张志丽，王孝伟，刘俊义*   

  1. (北京大学药学院化学生物学系 北京 100191)
  • 收稿日期:2011-04-17 修回日期:2011-05-20 发布日期:2011-06-10
  • 通讯作者: 刘俊义 E-mail:jyliu@bjmu.edu.cn

Synthesis and Bioactivity of N5-Substituted 4-Amino-N8,N10-deazatetrahydrofolate Analogues

TIAN Chao, LI Chao, ZHANG Zhi-Li, WANG Xiao-Wei, LIU Jun-Yi   

  1. (Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191)
  • Received:2011-04-17 Revised:2011-05-20 Published:2011-06-10

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以2,4-二氨基-6-羟甲基吡啶并[3,2-d]嘧啶为原料, 与对甲酰基苯甲酰谷氨酸二乙酯发生Wittig反应构建叶酸类似物的骨架结构, 还原吡啶环得到4-氨基-8,10-二碳杂四氢叶酸类似物, 在N5位取代不同基团得到四个新的4-氨基-N8,N10-二碳杂四氢叶酸类化合物, 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, 此类化合物对人重组胸苷酸合成酶的抑制作用与N5位取代基有关, 2个化合物在0.1 μmol•L－1的浓度下对HL-60白血病细胞的抑制率达到60%以上.

关键词: 4-氨基-N8,N10-二碳杂四氢叶酸类似物, 胸苷酸合成酶, 抗癌活性

The backbone of folate analogue was constructed via Wittig reaction between 2,4-diamino-6- hydroxymethylpyrido[3,2-d]pyrimidine and di-ethyl-N-[4-(formyl)benzoyl]-L-glutamate. Four new 4-amino- N8,N10-deazatetrahydrofolate analogues were obtained by hy-drogenating of pyridine ring and linking different substituent on N5 position. The compounds were characterized by 1H NMR, 13C NMR and MS techniques. The inhibitory activities against human thymidylate synthetase were determined. The results showed that the bioactivities of the compounds were related with different substituents on N5 position. The inhibitory rates of two compounds against leukemia cell line HL-60 were above 60% at 0.1 μmol•L－1.

Key words: 4-amino-N8,N10-deazatetrahydrofolate analogue, thymidylate synthetase, anticancer activity