Curvulinic Acid–Gregatin Hybrids with Anti-inflammatory Activity from a Soil-Derived Fungus Penicillium sp. KYS-21

Chemical investigation of the fungus Penicillium sp. KYS-21 resulted in the isolation of 16 new curvulinic acid–gregatin hybrids (CAGHs), penicurgretides A–P ( 1 – 16 ), together with the only known analogue ( 17 ) of this rare class of natural products. Their structures were unambiguously determined by comprehensive spectroscopic analyses, ECD calculations, single-crystal X-ray diffraction, and the modified Mosher’s method. These hybrids exhibit remarkable diversity, featuring a conserved R -configuration at C-5 but variable stereochemistry at other chiral centers. The α,β,γ,δ-unsaturated ketone in the C-5 side chain was established as a critical pharmacophore, as penicurgretides A ( 1 ) and G ( 7 ), bearing this moiety, exhibited moderate anti-inflammatory activity with IC 50 values of 2.94 ± 0.54 and 3.50 ± 0.52 μM, respectively. Mechanistic studies revealed that penicurgretide A ( 1 ) suppresses inflammation through inhibition of the NF-κB and mitogen-activated protein kinase signaling pathways, with in vivo efficacy confirmed by reducing nitric oxide and ROS production in an LPS-induced zebrafish model. These findings expand the structural diversity of CAGHs and highlight penicurgretide A ( 1 ) as a promising lead for anti-inflammatory drug development.