Abstract
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 C6-C7 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.
Highlights
Fungi have attracted much attention of chemists and biologists due to their potential in producing bioactive secondary metabolites with diverse chemical skeletons [1,2]
In order to explore in depth this kind of compounds with unique chemical structure and diverse biological activities, we explored Penicillium strains collected in our lab searching for verrucosidin analogues
The MS/MS-based molecular networking strategy was applied for target isolation of new verrucosidins
Summary
Fungi have attracted much attention of chemists and biologists due to their potential in producing bioactive secondary metabolites with diverse chemical skeletons [1,2]. Verrucosidins produced by Penicillium strains belong to a family of highly reducing fungal polyketides that are characterized with 2H-pyran-2-one and dicyclic fused 3,6-dioxabicyclo[3.1.0]hexane moieties interlinked by a polyene chain [3,4,5,6]. They have been reported to display important bioactivities, such as antitumor [7,8], antivirus [9], antibacterial [3,10], and neurological activities [11]. To explore new reducing fungal polyketides from fungi, we applied the LC-MS/MS-based molecular networking for new verrucosidins from Penicillium strains using deoxyverrucosidin that was deposited in our compound library as the probing agent
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