具有Src激酶和NO合酶双重抑制作用的4-芳杂胺-3-氰基喹啉类抗肿瘤化合物的设计、合成与生物活性研究

The design, synthesis and anticancer activity of 4-heteroarylamino-3-cyanoquinolines as dual inhibitors of c-Src and iNOS

摘要:
Src与iNOS为肿瘤发生、转移中位于不同通路的重要靶酶，本文采用分子拼合的药物设计原理，设计合成了全新的酪氨酸Src蛋白激酶与iNOS的双重抑制剂。所设计合成的化合物经过Src激酶和iNOS的抑制活性检测及体外抗肿瘤测试，实验结果表明大部分化合物对于两种靶酶均表现出一定的抑制活性，部分化合物对于多种肿瘤细胞的增殖有一定的抑制作用。其中化合物33对Src激酶和iNOS均有比较好的抑制活性，对于肝癌HepG2和结肠癌HT-29细胞的增殖也有明显的抑制作用。

Abstract:
Because c-Src and iNOS are key regulatory enzymes in tumorigenesis, a new series of 4-heterocycle amine-3-quinolinecarbonitriles as potent dual inhibitors of both enzymes were designed, synthesized and evaluated as multiple targets agents in cancer therapy. All compounds were evaluated by two related enzyme inhibition assays and an anti-proliferation assay in vitro. The results showed that most compounds inhibited c-Src and iNOS well. The best compound 33 inhibited both enzymes with the IC₅₀ values of 0.048 4 μmol×L^-¹ and 34.5 μmol×L^-¹, respectively. Some of the compounds also showed moderate anti-proliferation activities at 10 μmol×L^-¹ against colon cancer HT-29 and liver cancer HepG2 cell lines.