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有机化学
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有机化学 ›› 2011, Vol. 31 ›› Issue (01): 75-81. 上一篇    下一篇

研究论文

N-{4-{N-甲基-N-[2-羟基-3-(2,4-二氧代-1,2,3,4-四氢嘧啶-5-基)氨基]丙基}氨基-3-溴}苯甲酰基-L-谷氨酸二乙酯及其衍生物的合成

邓喜玲1,3，刘卫东1，李超1，张志丽1，王孝伟1，刘俊义*,1,2   

  1. (1北京大学药学院化学生物学系 北京 100191)
    (2北京大学天然药物及仿生药物国家重点实验室 北京 100191)
    (3石河子大学药学院药学系 石河子 832002)
  • 收稿日期:2010-03-12 修回日期:2010-07-05 发布日期:2010-08-12
  • 通讯作者: 邓喜玲 E-mail:xjdengxiling@bjmu.edu.cn
  • 基金资助:

    国家自然科学基金;国家博士点基金

Synthesis of Diethyl N-{4-[N-Methyl-N-(3-(2,4-dioxo-1,2,3,4- tetra-hydropyrimidin-5-yl)amino-2-hydroxypropyl)amino]- ben-zoyl}-L-glutamate and Its Derivatives

Deng Xiling1,3 Liu Weidong1 Li Chao1 Zhang Zhili1 Wang Xiaowei1 Liu Junyi*,1,2   

  1. (1 Department of Chemical Biology, School of Pharmaceutical Sciences, Peking Univer-sity, Beijing 100191)
    (2 State Key Laboratory of Natural and Biomimetic Drug, Peking University, Beijing 100191)
    (3 Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences, Shihezi University, Shihezi 832002)
  • Received:2010-03-12 Revised:2010-07-05 Published:2010-08-12
  • Contact: DENG Xi-Ling E-mail:xjdengxiling@bjmu.edu.cn

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报道了N-{4-{N-甲基-N-[2-羟基-3-(2,4-二氧代-1,2,3,4-四氢嘧啶-5-基)氨基]丙基}氨基-3-溴}苯甲酰基-L-谷氨酸二乙酯及其衍生物的简便合成方法. 分别以4-氨基苯甲酸乙酯和4-氨基苯甲酰基-L-谷氨酸二乙酯为起始物, 经甲基化、烯丙基化、溴羟基化、环氧化、开环、脱保护等反应首次合成了6个新型5-取代氨基嘧啶类化合物, 并通过1H NMR, 13C NMR 和MS对其化学结构进行了表征. 初步生物活性结果表明, 苯环侧链的L-谷氨酸酯部分是此类化合物抑制人重组二氢叶酸还原酶的必需结构.

关键词: 5-取代氨基嘧啶, 新型抗肿瘤化合物, 合成

A new practical approach to prepare diethyl N-{4-[N-methyl-N-(3-(2,4-dioxo-1,2,3,4-tetrahy-dropyrimidin-5-yl)amino-2-hydroxypropyl)amino]benzoyl}-L-glutamate and its derivatives has been realized from ethyl 4-aminobenzoate (4a) and diethyl N-(4-aminobenzoyl)-L-glutamate (4b). Six novel 5-(substituted)amino pyrimidines 9～11 were synthesized via methylation, allylation, bromohydroxylation, epoxidation, ring-opening, deprotection reaction and so on, and were characterized by 1H NMR, 13C NMR and MS techniques. The inhibitory activities against human dihydrofolate reductase of the compounds have been determined. The results showed that the bioactivities of the compounds were related with L-glutamate side chain.

Key words: 5-(substituted)amino pyrimidine, new anticancer agent, synthesis