1,2,3-三唑并哌嗪（酮）及1,2-异噁唑并哌啶酮类Hsp90抑制剂先导化合物的优化与抗肿瘤活性评价

Heat shock protein 90 (Hsp90) is a recently recognized important target of cancer chemotherapy. Nearly 20 small molecule Hsp90 inhibitors are currently under clinical trials for their potential in treatment of cancer. A group of novel heterocyclic Hsp90 inhibitors were discovered in our previous study. These compounds were easily prepared by utilizing an intramolecular dipolar cycloaddition reaction, and showed significant anticancer activities in vitro (IC50 1-10 μM) and in vivo as well. This project is therefore aiming at a further structural optimization by adopting this group of active compounds as leads, without altering the basic synthetic strategy. With the retained key resorcinolic pharmacophore, structural variants referring motif A and B in these molecules will be screened for an insight of structure-activity relationships. In addition to the empirical approach of molecular design, computer assisted rational design is also to be attempted in this study.

热休克蛋白90(Hsp90)是一个最近才得到认识的重要抗肿瘤药物作用靶点，目前有近20个小分子Hsp90抑制剂处于临床研究。本课题组在前期工作中发现了一类结构新颖的杂环类Hsp90抑制剂。此类化合物可以利用分子内偶极环加成方法简便地合成，体外抗肿瘤活性较好（IC50 1-10 μM）且体内有效。本项目拟以这些活性化合物为先导，保留其间苯二酚药效团，继续利用分子内偶极加成反应，对该类分子中可变的A、B两个片断进行有序的优化，考察构效关系，争取使化合物活性有实质性的提高。本项目的结构优化思路既包括了经验设计方法，也考虑尝试计算机辅助理性设计方法。

本项目首先按计划进行了1,2,3-三唑并哌嗪（酮）及1,2-异噁唑并哌啶酮类Hsp90抑制剂先导化合物的优化与抗肿瘤活性评价工作。共计完成了三百余个新化合物的设计、合成与生物学评价，肯定了此类结构的药学研究前景，对其中的A、B片段结构与活性的关系作出了较为明确的结论，发现了一批体外活性优良的新结构Hsp90抑制剂。. 项目还开展了有关天然产物Hsp90抑制剂，即苯安莎霉素类天然产物，的全合成以及基于全合成技术的构效关系研究，完成了两个此类化合物的全合成、并以此为基础对其中的Herbimycin A进行了初步构效关系探讨，为解决此类化合物的肝毒性问题提供了新的手段和方法。.在本项资助下，共计发表SCI论文8篇，培养研究生8名。