Structure and Biosynthesis of Perochalasins A-C, Open-Chain Merocytochalasans Produced by the Marine-Derived Fungus sp. M16.

Novel open-chain merocytochalasans, perochalasins A-C (-), containing an unusual N-O six-membered heterocyclic moiety, were isolated from cultures of the marine-derived sp. M16 fungus, along with cytochalasin Z (), cytochalasin Z (), [12]-cytochalasin (), and phenochalasin B (). The structures of compounds - were established by analysis of the spectroscopic data. Full genome sequencing of sp. M16 enabled the identification of a cytochalasan biosynthetic gene cluster and a proposal for the biosynthetic assembly of perochalasins. The proposal is supported by the nonenzymatic conversion of phenochalasin B () into -, based on isotope-labeled hydroxylamine (NHOH and NDOD) feeding studies and . In contrast to other merocytochalasans, these are the first cytochalasans confirmed to arise via nucleophilic addition and at a distinct location from the reactive macrocycle olefin, potentially expanding further the range of merocytochalasans to be discovered or engineered. Cytochalasin Z () exhibited antiplasmodial activities in the low micromolar range against the chloroquine-sensitive 3D7 strain as well as against resistant strains of the parasite (Dd2, TM90C6B, and 3D7r_MMV848).