Modulating culture method promotes the production of disulfide-linked resorcylic acid lactone dimers with anti-proliferative activity.

Sulfur-containing natural products are distinguished by their unique chemical structures and notable biological activities, rendering them highly valuable in drug discovery and development. Recent advancements in chemical epigenetic modifications, sulfur source regulation, and fungal co-cultivation have significantly facilitated the discovery of novel sulfur-containing compounds. In this study, the modulating culture method, incorporating DMSO and sea salt into the culture medium, was utilized to induce the marine-derived fungus Penicillium sp. to produce novel disulfide-linked resorcylic acid lactone dimers, dipenirestone A and B (1 and 2), along with their monomeric precursors (3-13). The absolute configurations of the new compounds 1-6 were elucidated through calculated NMR and ECD methods, as well as X-ray crystallography. Notably, the dimeric compounds (1 and 2) exhibited significantly enhanced anti-proliferative activity against HGC-27 cells compared to the monomers 3-13. It was revealed that compounds 1 and 2 exerted an antiproliferative effect through the modulation of the PI3K/AKT/mTOR signaling pathway. This was manifested as cell cycle arrest in the G1 phase, reduction in mitochondrial membrane potential, and induction of apoptosis.