Xylarols A-G, structurally diverse specialized metabolites from mangrove endophytic fungus Xylaria sp. AH-75 and their anti-colorectal cancer activities.

Seven previously undescribed compounds including three steroids xylarols A-C (1-3), two sesquiterpenoids xylarols D (4) and E (5), and two polyketides xylarols F (6) and G (7) together with five known related derivatives (8-12) were isolated from the mangrove endophytic fungus Xylaria sp. AH-75. Their structures were elucidated through comprehensive spectroscopic analysis, quantum chemical calculations (13C NMR-DP4+ analysis and calculated ECD), and the single-crystal X-ray diffraction analysis. Xylarol D (4) is a rare 4/7/4 tricyclic sesquiterpenoid and represents the first example with 13,14-dihydoxy. The growth-inhibitory activities of compounds 1-7 were evaluated against four colorectal cancer cell lines (HCT-116, SW480, CT26, and MC38), among which xylarols A (1) and B (2) exhibited potent inhibitory effects (IC50 = 2.30-13.97 μM). Further mechanistic studies revealed that compound 2 suppressed the proliferation of HCT-116 and SW480 cells by inducing G1 phase cell cycle arrest and apoptosis, which was accompanied by activation of caspase-dependent apoptotic signaling and regulation of Bax/Bcl-2-mediated mitochondrial pathways.