几种高等真菌中杂合倍半萜类成分研究及其活性评价

Novel compounds found in higher fungi have significant biological activity and play a very important role in drug discovery. Among them, merosesquiterpenoids could increase the probability of finding potential active compounds. The structures of those chemical compositions containing biological characteristics of both sesquiterpenoid and heterozygous fragment, could be a boon to drug discovery. Our research group found new merosesquiterpenoids showed significant activity: albaconol, a antagonist to VR-1（IC50 = 5 μM）; craterellin A demonstrated strong inhibitory activities against human 11beta-HSD2 with IC50 value of 1.5 μg/mL. In order to obtaine a wide variety of merosesquiterpenoids, this project intends to take the advantage of the rich higher fungi resources in southwest China, focusing on isolation and structure elucidation of such metabolites from fruiting bodies and culture broth. Combination with using variety of enzymes and cell-based screening assays, we expect to found new structures which have supremely high active.

高等真菌中结构新颖和具有显著生物活性的次生代谢产物对于药物先导化合物的发现非常重要，而其中的杂合倍半萜因其结构为倍半萜和其它片段杂合形成，兼具倍半萜和杂合片段的活性潜质，能有效提高发现苗头分子的概率，继而为新化学实体药物的创制提供源泉。我们研究组近期陆续发现了有较高生物活性的该类新结构：地花菌素albaconol具有vanilloid receptor-1 (VR-1)受体拮抗作用（IC50 = 5 μM）；craterellin A对人的11beta-HSD2有显著抑制作用（IC50 = 1.5 μg/mL）。为了获得更多此类成分，继而开展系统深入的活性评价，本项目拟利用我国西南地区丰富的高等真菌资源为研究对象，重点分离鉴定杂合倍半萜类次生代谢产物，以期获得一系列新结构，丰富杂合倍半萜的结构类型，并利用各种酶、细胞筛选模型，从中寻找和发现高活性化合物。

系统研究了三种地花菌属子实体、三批次芳香喇叭菌发酵液和白心灵芝子实体的化学成分及其抗肿瘤、白色念珠菌耐药逆转和脂肪酶抑制的活性研究。1）从5种高等真菌（地花菌属3种、喇叭菌属1种和灵芝属1种）中共分离鉴定了126个化合物其中杂合倍半萜37个。新化合物46个其中杂合倍半萜10个，包括一个新骨架杂合倍半萜；2）新骨架杂合倍半萜以消旋非对称二聚体形式存在。该杂萜对胰脂肪酶显示出强抑制活性：消旋体抑制活性为27.3 μM，右旋体和左旋体抑制活性分别为4.0 μM和2.5 μM。3）另有两个新杂合倍半萜成分分别显示了很强的白色念珠菌氟康唑临床耐药株耐药逆转和一定的抗肿瘤活性。研究中发现的有显著活性的新结构成分为寻找新的胰脂肪酶抑制剂和抗耐药性真菌感染的药物研究打下了良好的物质基础。