Astellolides R–W, Drimane-Type Sesquiterpenoids from an Aspergillus parasiticus Strain Associated with an Isopod

Sesquiterpenoids with a cage-like multiring frame are rarely found in nature. Mining of the isopod-derived fungus Aspergillus parasiticus SDU001 by the one strain–many compounds (OSMAC) strategy unexpectedly led to the discovery of fungal drimane-type sesquiterpenoids astellolide R (1), featuring an unusual cage-like 6/6/5/6/5 pentacyclic ring system, astellolide S (2), possessing a rare nicotinic acid building block, and astellolides T–W (3–6). Their structures were comprehensively assigned by spectroscopic data analysis, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Furthermore, compounds 3 and 5 exhibited anti-inflammatory activity by inhibiting the lipopolyssacharide-induced NO production in RAW264.7 macrophages with IC50 values of 6.1 ± 0.8 and 6.8 ± 0.8 μM, respectively. A putative biosynthetic pathway for 1 is proposed. Our results enlarge the chemical space of the drimane-type sesquiterpenoids generated from endophytic fungi.

具有笼状多环骨架的倍半萜类化合物在自然界中极为罕见。本研究采用一菌多产物（OSMAC）策略，对一株等足目来源的寄生曲霉（Aspergillus parasiticus）SDU001的次级代谢产物进行挖掘，意外发现了6个真菌drimane型倍半萜类化合物：具有罕见笼状6/6/5/6/5五环骨架的astellolide R（1）、带有罕见烟酸结构单元的astellolide S（2），以及astellolide T至W（3~6）。通过光谱数据分析、单晶X射线衍射以及电子圆二色性计算，对所有化合物的结构进行了全面解析。此外，化合物3和5可通过抑制脂多糖诱导的RAW264.7巨噬细胞一氧化氮（NO）生成展现抗炎活性，其半数抑制浓度（IC50）分别为6.1 ± 0.8 μM和6.8 ± 0.8 μM。本研究提出了化合物1的推测生物合成途径。本研究结果拓展了内生真菌来源的drimane型倍半萜类化合物的化学空间。