新型甲氨蝶呤衍生物的合成

设计合成了新的甲氨蝶呤(methotrexate, MTX)衍生物1～4, 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1～4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2和4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.

Synthesis of Novel Methotrexate Derivatives

A series of novel methotrexate (MTX) derivatives (1～4) 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.