具有抗肿瘤活性的吲哚衍生物的设计合成及活性研究

In the contemporary world, tumor has become the mankind’s first killer, which is becoming a great threat to the human’s life and health. Protein tyrosine kinases are composed of vascular endothelial growth factor receptor (VEGFR), etc. VEGFR is the key to promote vascular growth factors in new angiogenesis. VEGFR is usually high expression in tumor blood vessels, so VEGFR is an ideal target of anti-tumor angiogenesis. The research and development of VEGFR inhibitours is hopeful to overcome the toxic and side effects and drug resistance of present anti-cancer drugs..This research project adopts the method of computer aided design to synthesis of the indole derivatives library 1 basing on the lead compound BIBF-1120 of VEGFR inhibitors. Similarly, based on lead compound AEE788 of VEGFR inhibitors, we design the indole derivatives library 2~3. Then, we will study the antitumor activity based on VEGFR-2 in vitro and structure-activity relationship of the three kinds of indole derivatives libraries containing 90~120 compounds. And on this base, optimism 2~3 compounds in vitro models of tumor cells will be used as in vivo antitumor screening animal model, pharmacokinetic studies and acute toxicity studies in mice. This project is hopeful for finding better activities and high selectivity VEGFR inhibitors 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。酪氨酸激酶包括血管内皮细胞生长因子受体 (VEGFR) 等多种。VEGFR 是新生血管生成中的关键性促血管生长因子, VEGFR 在肿瘤血管中高表达，是抗肿瘤血管生成的理想靶点。VEGFR 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。.本项目以 VEGFR 抑制剂 BIBF-1120 为先导化合物采用计算机辅助设计吲哚衍生物库 1。而以 VEGFR 抑制剂 AEE788 为先导化合物设计吲哚衍生物库 2~3。我们将对这三类吲哚衍生物库共 90~120 个化合物针对 VEGFR-2 的体外和体内抗肿瘤活性筛选及构效关系研究。在此基础上，优选2~3个活性较好的化合物进行药代动力学研究和小鼠体内急毒性研究。通过本项目的完成有望发现高效和高选择性 VEGFR-2 抑制剂或先导化合物。

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。本项目以酪氨酸激酶抑制剂 BIBF-1120 、AEE788为先导化合物采用计算机辅助设计吲哚衍生物库 1~3。.本项目用杂环烯酮缩胺及其衍生物为合成砌块，一锅法高效平行合成十多类吲哚、吡咯、喹啉等杂环化合物。所合成部分化合物用四氮唑盐法进行体外抗肿瘤活性测试，部分化合物具有较好的生物活性，优先部分化合物进行激酶包括VEGFR-2 激酶、EGFR和CDC25B激酶活性筛选，筛选发现所设计部分化合物具有较好的抑制CDC25B激酶的抑制活性，而对EGFR有一定活性，而没有抑制VEGFR-2 激酶的抑制活性。优先1个化合物用 Western blot 法检测细胞凋亡机制研究,初步获得两个抗肿瘤先导化合物3u, 4w'。此外完成任务书以外的部分化合物的抗肿瘤、免疫抑制活性研究，完成一类化合物的抗菌活性初筛、复筛及酶抑制活性、药代动力学研究、成功筛选到2个抗菌先导化合物 16a', 16b'。这两个先导化合物在今后的研究中有望成为药物或前药。