Aculeatones A and B, epimeric lovastatin derivatives with a 6/6/3-tricyclic carbon skeleton from Aspergillus aculeatus and their chemical transformation

Abstract

Lovastatin and its derivatives are well-known as a class of lipid-lowering drugs in the medicinal chemistry of natural products, and they typically feature a rigid decalin core structure with almost no other carbon rings. Herein, aculeatones A (1) and B (2), two highly modified lovastatin derivatives with an unreported 6/6/3-tricyclic carbon skeleton, in addition to four undescribed lovastatin derivatives aculeatones C–F (3–6), were isolated from the fungus Aspergillus aculeatus. Their structures with absolute configurations were characterized by comprehensive spectroscopic, quantum chemical calculation, electronic circular dichroism (ECD), modified Mosher's method, and single-crystal X-ray diffraction studies. The plausible biosynthetic pathway for 1 and 2 was proposed, and the biomimetic formation of 1 was achieved starting from 3. Biologically, compounds 3, 5, and 6 significantly inhibited the accumulation of lipid in an oleic acid-treated HepG2 cell model.