多环喹啉衍生物的设计、合成及抗肿瘤活性研究

In the contemporary world, cancer has become the mankind's first killer, which is becoming a great threat to the human's life and health. Topoisomerase can control the topology structure of DNA by catalysis DNA chain break and binding. It's generally acknowledged that Topoisomerase I is a useful therapeutic target against tumor growth. The research and development of Topoisomerase I inhibitours is hopeful to overcome the toxic and side effects and drug resistance of present anti-cancer drugs. Quinoline derivatives can be inhibit the activities of topoisomerase I, and show the excellent antitumor activity. This research project using quinoline derivative (Nothapodytine B) as a lead compound, the libraries of polycyclic quinolines were designed and synthesized. A simple synthesis of 80-100 target compounds via heterocyclic ketene aminal reaction with substituted quinolines in one-pot. Attempt to study the antitumor activity and structure-activity relationship of these compounds. This project is hopeful for finding better activities and high selectivity antitumor drugs or lead compounds.

肿瘤是当今世界严重威胁人类生命与健康的疾病，成为死亡的头号杀手。拓扑异构酶可通过 催化DNA 链的断裂和结合控制其拓扑结构。拓扑异构酶 I 成为公认的抗癌药作用靶点。拓扑异构酶 I 抑制剂的研究开发有望解决目前临床抗肿瘤药物毒副作用及抗药性等问题。喹啉类化合物可有效抑制拓扑异构酶 I 从而表现出十分优越的抗肿瘤活性。本项目以喹啉类化合物Nothapodytine B 为先导化合物设计合成多环喹啉衍生物库。并用杂环烯酮缩胺与取代喹啉一锅法简便合成80-100 个目标化合物。拟对其进行抗肿瘤活性测试及构效关系研究。通过本项目的完成极有希望发现高效和高选择性的抗肿瘤药物或先导化合物。

肿瘤是当今世界严重威胁人类生命与健康的疾病，成为死亡的头号杀手。喹啉类化合物是潜在的拓扑异构酶 I 抑制剂。本项目以拓扑异构酶 I 抑制剂Nothapodytine B为先导化合物设计合成多环喹啉衍生物库。对其进行抗肿瘤活性测试及构效关系研究。通过本项目的完成极有希望发现高效和高选择性的抗肿瘤药物或先导化合物。.用杂环烯酮缩胺(HKAs)为合成砌块，一锅法高效平行合成20个多环喹啉类化合物4。我们又用杂环烯酮缩胺为砌块设计合成25个多环喹啉类化合物5。所合成化合物4-5用四氮唑盐法进行体外抗肿瘤活性测试，化合物4-5对HCT116, NCI-H460, SK-OV-3, HT29和A549的细胞毒活性较好，接半数化合物抗肿瘤活性与顺铂相当；其中化合物5u, 5w, 5x 对十二中肿瘤细胞株的细胞毒活性具有普适性，且效果好，有望成为先导物。.建立了通过邻氟苯甲醛与杂环烯酮缩胺串联反应一步法合成喹啉类化合物5-1的方法，共合成48个喹啉化合物。用杂环烯酮缩胺或1,1-烯二胺(EDAMs)为反应砌块，合成了23个异喹啉类化合物5-3和5-4; 69个喹啉类化合物5-5~5-7; 33个喹唑啉类化合物5-8。对所合成的化合物用四氮唑盐法进行体外抗肿瘤活性测试，其中化合物5-1ao, 5-3s, 5-3t, 5-8w and 5-8x具有优越的抗肿瘤活性。在此基础上，喹唑啉类化合物5-8筛选其抑制蛋白磷酸酶CDC25B活性，研究表明，5-8w and 5-8x对蛋白磷酸酶CDC25B具有明确的抑制活性。综合来看，化合物5u, 5w, 5x 5-1ao , 5-3s, 5-3t, 5-8w 和5-8x在今后的研究中有望成为前药或药物。