Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 (China).
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204 (China).
Angew Chem Int Ed Engl. 2015 Nov 2;54(45):13374-8. doi: 10.1002/anie.201506264. Epub 2015 Sep 3.
Asperchalasine A (1), the first cytochalasan dimer featuring a unique decacyclic 5/6/11/5/5/6/5/11/6/5 ring system consisting of 20 chiral centers, was isolated from the culture broth of Aspergillus flavipes. Three biogenetically related intermediates, asperchalasines B-D (2-4), were also isolated. Their structures, including their absolute configurations, were elucidated using a combination of HRESIMS, NMR, ECD, molecular modeling, and single-crystal X-ray diffraction techniques. Compound 1, which possesses an unprecedented 13-oxatetracyclo[7.2.1.1(2,5).0(1,6)]tridec-8,12-dione core structure, is the first example of a dimeric cytochalasan alkaloid. The biogenetic pathways of 1-4 were described starting from the co-isolated compounds 5 and 6. More importantly, 1 induced significant G1-phase cell cycle arrest by selectively inhibiting cyclin A, CDK2 and CDK6 in cancerous, but not normal, cells, highlighting it as a potentially selective cell cycle regulator against cancer cells.
从土曲霉（Aspergillus flavipes）的发酵液中分离得到了化合物 1，它是第一个具有独特的二十个手性中心组成的二十元双环[5/6/11/5/5/6/5/11/6/5]稠合环系的细胞松弛素二聚体，结构新颖。还分离得到了三个生物相关的中间体，asperchalasines B-D（2-4）。通过高分辨质谱（HRESIMS）、核磁共振（NMR）、圆二色谱（ECD）、分子建模和单晶 X 射线衍射技术等手段确定了它们的结构，包括绝对构型。化合物 1 具有前所未有的 13-氧杂十六环[7.2.1.1(2,5).0(1,6)]十三烷-8,12-二酮核心结构，是第一个二聚细胞松弛素生物碱的例子。从共分离得到的化合物 5 和 6 出发，描述了 1-4 的生物合成途径。更重要的是，1 通过选择性抑制癌细胞而非正常细胞中的细胞周期蛋白 A、CDK2 和 CDK6，诱导显著的 G1 期细胞周期停滞，这表明它是一种潜在的选择性细胞周期调节剂，可用于对抗癌细胞。
