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以氯乙腈和2-噻吩甲醛为原料,通过接合经缩合、环合、还原、硝化等步骤合成的两个关键中间体1c和2d,设计合成了两个新型二氢叶酸还原酶抑制剂的衍生物3c和4b,其结构经1H NMR、13C NMR和MS方法验证.采用噻唑蓝法对目标化合物进行了抗肿瘤活性测试,结果表明3c对筛选的5种肿瘤细胞株的抑制活性均比阳性对照药洛美曲索、甲氨蝶呤和培美曲塞强,4b对Hep-G2的抑制活性比阳性对照药洛美曲索、甲氨蝶呤和培美曲塞强,而且3c和4b对正常细胞株——人脐带内皮血管平滑肌细胞的抑制活性明显比甲氨蝶呤和培美曲塞弱.
Using chloroacetonitrile and 2-thiophenecarboxaldehyde as raw materials, two new derivatives of dihydrofolate reductase inhibitors were designed and synthesized by bonding the two key intermediates 1c and 2d, which were synthesized by the steps of condensation, cyclization, reduction and nitration. The structures of compounds 3c and 4b were confirmed by 1H NMR, 13C NMR and MS.The antitumor activity of the target compounds was tested by thiazolyl blue method.The results showed that the inhibitory activity of 3c against the 5 selected tumor cell lines was higher than that of the positive control Methotrexate and pemetrexed were more potent than those of 4b, and the inhibitory activity of 4b on Hep-G2 was stronger than that of the positive control drugs lomefloxacur, methotrexate and pemetrexed, and the 3c and 4b pairs The inhibitory activity of normal human umbilical cord endothelial cells on vascular smooth muscle cells was significantly lower than that of methotrexate and pemetrexed.