Penidaleodiolides A and B, Cage-Like Polyketides with Neurotransmission-Regulating Activity from the Soil Fungus L3SO.

L3SO is a fungus isolated from the rhizospheric soil of the chloroplast-deficient plant . A chemical study on the rice fermentation of this fungus led to the isolation and identification of two cage-like polyketides, penidaleodiolide A () and its biosynthetic-related congener penidaleodiolide B (). The structures of and were determined by a combination of extensive spectroscopic analysis, biosynthetic consideration, chemical derivatization, and computational methods. Compound harbors an unusual tricyclo[4.3.0]nonane scaffold, unprecedented in polyketide natural products. The hypothetical biosynthetic pathways for and were postulated and were supported by CRISPR/Cas9 genome editing results. Penidaleodiolide A () showed a significant inhibitory effect on the action potentials of murine hippocampal basket neurons and decreased the frequency of spontaneous excitatory postsynaptic currents in a concentration-dependent manner (the inhibition ratios were 0.30 ± 0.02 for 1 μM, 0.37 ± 0.03 for 10 μM, and 0.50 ± 0.07 for 20 μM) while being devoid of cytotoxicity against the nerve cells.