Unveiling the Mechanisms of Apoptosis Induction by Deep-Sea-Derived Polyketide-Terpenoid Hybrids from Penicillium allii-sativi: A Focus on Mitochondrial and mTOR Pathways

Abstract

A chemical investigation of the deep-sea-derived fungus Penicillium allii-sativi MCCC 3A00580 resulted in the discovery of four new meroterpenoids (1—4) and one related known co-metabolite (5). These meroterpenoids showcase unique carbon skeletons featuring a common drimane sesquiterpene part with highly diverse polyketide units. Particularly, compound 1 incorporates a salicylic acid moiety while 2 possesses a rare peroxide bridge in the polyketide part. The structures of new compounds were assigned by extensive spectroscopic analysis, quantum calculations, and biogenetic considerations. Notably, 3 significantly blocked the mTOR signaling pathway, resulting in the arrest of cell cycle at G0-G1 phase and triggering mitochondrial apoptosis in Hela cells. While the previously reported co-metabolite macrophorin A (MPA) effectively triggered cell death in MDA-MB-231 cancer cells by activating apoptosis pathways involving death receptors, mitochondria, mTOR, and TNF.