抗肿瘤活性细胞松弛素类生物碱的全合成研究

Historically, nature products have been widely used and played an essential role in the area of anticancer drug discovery. Many cytochalasans alkaloids have been reported to exhibit significant anticancer activities. The combination of striking 5/6/11/5/5/6/5/11/6/5 structure features and exciting anticancer bioactivity attracted us to develop a total synthetic route to asperchalasines A–D. We will initiate this project in three aspects. First, we will develop a concise and efficient approach to large scale synthesis of aspochalasin B2, which is the key intermediate for the synthesis of asperchalasine A. Secondly, we will develop a divergent route to asperchalasines A–D by using intermolecular Diels-Alder reaction of aspochalasin B2 and epicoccine, followed by 5+2 addition of aspochalasin B2 and advanced intermediate 2. Thirdly, we will investigate the 5+2 addition of α,β-unsaturated ketones with pyrogallols. The main goal of this program is to develop the first asymmetric total synthesis of anticancer alkaloids: asperchalasines A–D. This project may display the power and beauty of modern organic synthesis and also provide enough samples for pharmaceutical research.

细胞松弛素具有重要的抗肿瘤活性，而新型二聚类细胞松弛素asperchalasine A有望成为新的肿瘤细胞G1周期抑制剂。鉴于asperchalasine A重要的抗肿瘤活性和独特的5/6/11/5/5/6/5/11/6/5十环结构，本项目拟从三个方面开展asperchalasines A–D的全合成研究：1. 简洁、高效地合成关键中间体aspochalasin B2，为后续asperchalasine A的全合成提供原料。2. 利用分子间Diels-Alder反应及5+2关环策略实现asperchalasines A–D的仿生全合成。3. 建立邻苯三酚与α,β-不饱和烯酮构建[3.2.1]桥环骨架的合成方法学。本项目是对具有抗肿瘤活性细胞松弛素asperchalasine A的首次不对称全合成研究，既能展现现代合成化学的威力和重要意义，也可为该分子后续药理、药化的研究提供物质基础。

细胞松弛素是一大类包含异吲哚酮结构单元的三环真菌次生代谢产物，它们具有新颖多样的骨架结构和多样的生物活性，如杀线虫，抗炎，抗肿瘤等活性，是发现新颖药物先导化合物的重要来源。由于该类天然产物结构新颖且自然含量稀少，是近年来全合成领域的明星目标分子。我们课题组提出了一种基于生源分析的新策略，实现了从三环细胞松弛素到五环细胞松弛素和细胞松弛素多聚体的高效转化，共完成35个家族成员的系列全合成，为该类天然产物后续药物化学研究及生物合成途径解析提供了重要基础。在本项目支持下共发表SCI论文10篇，其中IF>10研究论文5篇，授权专利3项。