苔藓植物中贝壳杉烷类化合物的发现、结构多样性制备及靶向线粒体抗肿瘤作用研究

ent-Kaurane type of diterpenoids with α,β-unsaturated ketone moiety, as important drugable leads, are found to be effective leads in killing cancer cells. The challenge of these compounds to be developed into drugs is their high IC50 and low selectivity. Mitochondria, which are generally considered the cellular powerhouse, are small subcellular organelles that generate most cellular energy in the form of adenosine triphosphate (ATP). Compare with the normal cells, the mitochondria of cancer cells have high rate of glycosis, increased metabolism, high membrane potential as well as the apoptosis resistance. Thus mitochondria are recognized as one of the most important targets for new drug design in cancer. Our present research was to find ent-kurane diterpenoids from Chinese liverworts and to diversify them by chemical modification and covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to make them more mitochondria targeted in order to find more active and more selective candidates for further clinical application.

含有α,β-不饱和酮结构的贝壳杉烷二萜具有抗肿瘤活性，是重要的抗肿瘤先导化合物。但其活性弱，选择性差是该类化合物发展成为药物的巨大挑战。基于与正常细胞相比，肿瘤细胞线粒体具有更旺盛的代谢、更高的膜电势、更强的凋亡耐受等特点使其成为抗肿瘤药物设计的重要靶点。本课题在对苔藓中贝壳杉烷二萜进一步分离研究的基础上，利用增加药效团的方法，化学制备多样结构的衍生物，提高其生物活性，同时引入靶向线粒体的靶头基团，提高线粒体的靶向性，获得活性更强、选择性更高的候选化合物，并进一步研究其体内和体外抗肿瘤活性和作用机制，为发展新型抗肿瘤药物奠定研究基础。

含有α,β-不饱和酮结构的贝壳杉烷二萜具有抗肿瘤活性，是重要的抗肿瘤先导化合物。对野外采集9种苔藓进行系统萜类成分分离，进一步丰富了已构建的天然小分子库：新增化合物103个，新化合物24个；从苔藓及地衣内生真菌中分离化合物41个，新化合物24个；基于异甜菊醇（Isosteviol）骨架化学合成贝壳杉型二萜衍生物97个；利用利用发散性策略完成了四环二萜，两类杂萜等10个天然分子的首次不对称全合成。此外还探索苔藓植物的生物合成规律。相关成果发表在Angew Chem Int Ed Engl（2篇）、New Phytologist、Org. Lett (2篇)等杂志。.基于与正常细胞相比，肿瘤细胞线粒体具有更旺盛的代谢、更高的膜电势、更强的凋亡耐受等特点，对所分离和合成的小分子库进行抗肿瘤活性和靶向线粒体筛选，并对其线粒体靶向和作用机制进行深入探讨，发现新作用靶点Prdx I/II和VPS18等，新作用靶点和作用机制的揭示为新型抗肿瘤药物的发现提供了前期理论基础。成果发表在Signal Transduction and Targeted Therapy、Redox Biology、European Journal of Medicinal Chemistry等杂志