Cytotoxic Pentacyclic Benzoquinone Dimers Featuring a Cyclopropane-Bridged Cage-like Skeleton from <i>Penicillium hispanicum</i>

Two new pairs of pentacyclic benzoquinone enantiomers, (±)-penuinones A (<b>1a</b>/<b>1b</b>) and B (<b>2a</b>/<b>2b</b>), were isolated from the mangrove-derived fungus <i>Penicillium hispanicum</i> LA032 using LC-MS/MS-based molecular networking. The structures of new compounds were elucidated by spectroscopic analyses and quantum chemical ECD calculations. Structurally, compounds <b>1a</b>/<b>1b</b> and <b>2a</b>/<b>2b</b> possess a highly constructed 6/3/5/6/6 pentacyclic structure featuring a rare cyclopropane-bridged cage-like tricyclo[3.2.1.0^2,7]octane core skeleton. In addition, a plausible biogenetic pathway of <b>1a</b>/<b>1b</b> and <b>2a</b>/<b>2b</b> was proposed. All four compounds exhibited significant cytotoxicity against Hepa1-6 and Huh7 cell lines. Among them, compound <b>1b</b> exhibited the most potent cytotoxicity against Hepa1-6 and Huh7 cell lines with IC₅₀ values of 1.4 ± 0.44 and 3.0 ± 0.13 μM, respectively.