新型苯并磺内酰胺类小分子微管蛋白抑制剂的合成与抗肿瘤活性研究

项目名称： 新型苯并磺内酰胺类小分子微管蛋白抑制剂的合成与抗肿瘤活性研究

项目编号： No.30873134

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 金属学与金属工艺

项目作者： 刘兆鹏

作者单位： 山东大学

项目金额： 32万元

中文摘要： 本研究以微管蛋白为靶点，基于苯磺酰胺基药效团和多酚醚结构片段，设计构象限制的苯并磺内酰胺类小分子微管蛋白抑制剂，利用申请者独创的环合反应，构建了结构多样性多官能团化苯并磺内酰胺化合物群，取得如下成果：1）通过添加助剂碘的方法，解决了环合反应中存在的还原产物问题，探讨了TMSCl-NaI-MeCN试剂诱导的环合反应机制，合成了包括A环修饰的系列3位单取代五员环苯并磺内酰胺衍生物系列；2）利用三步反应，建立了A环修饰3位单取代五员环苯并磺内酰亚胺的简便、快速地合成方法；3）构建了包括含多酚羟基等多官能团化3位单取代六员环苯并磺内酰胺衍生物系列，明确了TMSCl-NaI-MeCN试剂诱导的环合反应机理；4）建立了N-芳基取代六员环苯并磺内酰胺和苯并磺内酰烯胺类衍生物的合成新方法，扩展了TMSCl-NaI-MeCN试剂诱导的新型环合反应的应用范围；5）共合成结构多样性苯并磺内酰胺衍生物108个；6）通过抗肿瘤细胞生长抑制试验和微管聚合活性实验等，探讨了各类苯并磺内酰胺衍生物的构效关系，发现了具有良好抗肿瘤活性、较低毒性和高选择性的N-芳基取代六员环苯并磺内酰胺和苯并磺内酰烯胺类衍生物。

中文关键词： 微管蛋白抑制剂；抗肿瘤；苯并磺内酰胺；TMSCl-NaI-MeCN; 环合反应

英文摘要： Microtubules are effective targets for the design of novel antitumor agents. Based on the benzenesulfonamide pharmacophore and the polyphenolic fragments and with the help of the computer aided drug design technology, we designed a series of conformationally restricted novel benzosultams as antimitiotic agents. Utilizing the TMSCl/NaI/MeCN reagent mediated cyclization discovered by the applicant, a benzosultam library with a diversity of structures were constructed. The results include: 1) In the prsence of catalytic amount of iodine, the TMSCl/NaI/MeCN reagent mediated cyclization could be applied for the synthesis of 3-monosubstituted five-membered benzosltams and those with A-ring modification. Iodine played a crucial role in the eliminating the reductive side reaction in the cyclization processes; 2) a novel simple three-step synthesis of 3-arylated A-ring substituted five-membered benzosulimines via the TMSCl/NaI/MeCN reagent mediated novel cyclization; 3) a series of 3-monosubstituted six-membered benzosultams with different functional groups and phenolic benzosultams were synthesized through the TMSCl/NaI/MeCN reagent mediated cyclization; 4) a novel method for the preparation of both N,3-diarylated six-membered benzosultams and benzosulenamines (unsuturated benzosultams) were developed by making use of the TMSCl/NaI/MeCN reagent mediated cyclization; 5) a total of 108 new benzosultam derivatives were synthesized; 6) these novel benzosltams were screened on tumor cell proliferation inhibitions assay and some of them were studied on the inhibition of tubulin polymerization, the structure-activity relationships were summarized. Some of the N,3-diarylated six-membered benzosultams and benzosulenamines exhibited good antitumor activities with low toxicity and higher cell selectivity, and will be valuable for further study.

英文关键词： tubulin inhibitors; antitumor; benzosultams; TMSCl-NaI-MeCN; cyclization