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

Abstract

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 IC₅₀ 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.