Andrastin-gregatin hybrids with anti-inflammatory activity from a soil-derived fungus Penicillium sp. KYS-21

Andrastin meroterpenoids and gregatin polyketides are two widely distributed classes of structurally distinct natural products (NPs); however, hybrids containing both frameworks, termed andrastin-gregatin hybrids (AGHs), remain exceptionally rare. In our search for anti-inflammatory NPs from natural sources, six AGHs (1-6) and three known monomers (7-9) were isolated from Penicillium sp. KYS-21, of which andragatins A-C (1-3) were identified as new compounds. All AGHs potently inhibit the production of nitric oxide (NO) in LPS-stimulated macrophages with IC₅₀ values within 10 μM, while the monomers are inactive. Andragatin A (1) suppresses inflammatory responses in vitro by concurrently inhibiting the NF-κB and MAPK pathways and exhibits dose-dependent anti-inflammatory activity in an LPS-induced zebrafish model. This work expands the chemical and biological diversity of the rare AGH family and highlights the hybrid scaffold as a promising pharmacophore for anti-inflammatory drug discovery.