化学学报 ›› 2006, Vol. 64 ›› Issue (3): 249-254. 上一篇    下一篇

研究论文

新型甲氨蝶呤衍生物的合成

唐锋1,郑国海2,姚其正*,1,吕刚1,周卫芬1,王秋娟1   

  1. (1中国药科大学药学院 南京 210009)
    (2中国人民解放军第105医院 合肥 230031)
  • 收稿日期:2005-04-13 修回日期:2005-10-21 出版日期:2006-02-14 发布日期:2006-02-14
  • 通讯作者: 姚其正

Synthesis of Novel Methotrexate Derivatives

TANG Feng1, ZHENG Guo-Hai2, YAO Qi-Zheng*,1, LÜ Gang1, ZHOU Wei-Fen1, WANG Qiu-Juan1   

  1. (1 School of Pharmacy, China Pharmaceutical University, Nanjing 210009)
    (2 105th Hospital, The People's Liberation Army of China, Hefei 230031)
  • Received:2005-04-13 Revised:2005-10-21 Online:2006-02-14 Published:2006-02-14
  • Contact: YAO Qi-Zheng

设计合成了新的甲氨蝶呤(methotrexate, MTX)衍生物14, 在这些新化合物中, 将MTX分子中10-位对氨基苯甲酰谷氨酸砌块移植到4-位, 同时在6-位引入苯环芳香基以及甲基等基团. 生物活性测试结果显示, 化合物14具有与MTX相似的抑制iNOS活性的作用; 相对于MTX, 选测的化合物24明显地增强了抑制K-562白血病细胞株生长的活性. 本研究为进行MTX的结构修饰开辟了新途径, 2-氨基-4-[N-(对氨基苯甲酰谷氨酸)-基]-6-取代基蝶啶衍生物可成为潜在的抗肿瘤候选药物被进一步研究.

关键词: 甲氨蝶呤衍生物, 四氢生物蝶呤, 一氧化氮合酶, 一氧化氮合酶抑制剂, 抗肿瘤

A series of novel methotrexate (MTX) derivatives (14) in which 4-position was substituted by 10-(p-aminobenzoyl glutamic acid) moiety of MTX and 6-position was arylated or methylated respectively were synthesized and their inhibitory activities against inducible nitric oxide synthase (iNOS) were studied. Some of them were tested for growth inhibitory activities against K562 leukemia cell simultaneously. All of them had the effect of inhibition of iNOS activity. In contrast to MTX, compounds 2 and 4 enhanced tumoricidal activity significantly. These studies show that we open up a new pathway of the structural modification of MTX, and 2-amino-4-[N-(p-aminobenzoyl glutamic acid)-yl]-6-alkyl/arylpteridine derivatives may be brought to potential antineoplastic candidates for further studies.

Key words: methotrexate derivatives, tetrahydrobiopterin, nitric oxide synthase, nitric oxide synthase inhibitor, antineoplastic