Discovery of Oxidized p‑Terphenyls as Phosphodiesterase 4 Inhibitors from Marine-Derived Fungi

Four new p-terphenyl derivatives, talaroterphenyls A–D (1–4), together with three biosynthetically related known ones (5–7), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Compounds 1–3 are rare p-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that 1–7 were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (ttpB–ttpE). These p-terphenyls (1–7) and 36 marine-derived terphenyl analogues (8–43) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and 1–5, 14, 17, 23, and 26 showed notable activities with IC50 values of 0.40–16 μM. The binding pattern of p-terphenyl inhibitors 1–3 with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (1), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-β1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, 1 could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5–20 μM. This study suggests that the oxidized p-terphenyl 1, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.