Exploring Verrucosidin Derivatives with Glucose-Uptake-Stimulatory Activity from Penicillium cellarum Using MS/MS-Based Molecular Networking.

Under the guidance of LC-MS/MS-based molecular networking, seven new verrucosidin derivatives, penicicellarusins A-G ( 3 - 9 ), were isolated together with three known analogues from the fungus Penicillium cellarum . The structures of the new compounds were determined by a combination of NMR, mass and electronic circular dichroism spectral data analysis. The absolute configuration of penicyrone A ( 10 ) was corrected based on X-ray diffraction analyses. Bioactivity screening indicated that compounds 1 , 2 , and 4 showed much stronger promising hypoglycemic activity than the positive drug (rosiglitazone) in the range of 25-100 μM, which represents a potential new class of hypoglycemic agents. Preliminary structure-activity relationship analysis indicates that the formation of epoxy ring on C 6 -C 7 in the structures is important for the glucose uptake-stimulating activity. The gene cluster for the biosynthesis of 1-12 is identified by sequencing the genome of P. cellarum and similarity analysis with the gene cluster of verrucosidins in P. polonicum .