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

Novel open-chain merocytochalasans, perochalasins A-C ( 1 - 3 ), containing an unusual N-O six-membered heterocyclic moiety, were isolated from cultures of the marine-derived Peroneutypa sp. M16 fungus, along with cytochalasin Z 27 ( 4 ), cytochalasin Z 28 ( 5 ), [12]-cytochalasin ( 6 ), and phenochalasin B ( 7 ). The structures of compounds 1 - 3 were established by analysis of the spectroscopic data. Full genome sequencing of Peroneutypa 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 ( 7 ) into 1 - 3 , based on isotope-labeled hydroxylamine ( 15 NH 2 OH and ND 2 OD) feeding studies in vivo and in vitro . 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 27 ( 4 ) exhibited antiplasmodial activities in the low micromolar range against the chloroquine-sensitive Plasmodium falciparum 3D7 strain as well as against resistant strains of the parasite (Dd2, TM90C6B, and 3D7r_MMV848).