Curvulinic Acid−Clavatol Hybrids and Curvulinic Acid Dimers with Anti-Inflammatory Activity from Penicillium sp. KYS-21

Abstract A chemical investigation of the fermentation broth of the soil-derived fungus Penicillium sp. KYS-21 led to the isolation of seven previously undescribed polyketide metabolites (1−7). Among them, penicurclavones A−D (1−4) represent the first examples of curvulinic acid−clavatol hybrids (CACHs). Penicurclavone A features a unique 6/6/6/6 tetracyclic ring system, while penicurclavones B−D share a distinctive 6/5/5/6 tetracyclic scaffold. Compounds 5−7 are characterized as curvulinic acid dimers, with 5 and 6 occurring as racemic mixtures. Heterologous expression of the key polyketide synthases (PKSs) enabled the identification of the biosynthetic gene clusters (BGCs) for curvulinic acid and clavatol, with the curvulinic acid BGC being discovered and characterized for the first time. Among the isolates, (−)-penicurclavone D (4) exhibits potent anti-inflammatory activity, with an IC50 value of 6.46 ± 1.48 μM. Mechanistic studies revealed that compound 4 suppresses the inflammatory response by inhibiting the NF-κB and MAPK signaling pathways, and its in vivo efficacy was further validated using a zebrafish model.