Discovery of a Phenylamine-Incorporated Angucyclinone from Marine Streptomyces sp. PKU-MA00218 and Generation of Derivatives with Phenylamine Analogues

Abstract

A new phenylamine-incorporated angucyclinone (1) featuring a unique 1-phenylbenzo­[cd]­indol-3­(1H)-one moiety was discovered from marine Streptomyces sp. PKU-MA00218. A series of experimental investigations identified that 1 was produced from the nonenzymatic conversion of a C-ring-cleaved angucyclinone (2) with phenylamine. Utilizing the nonenzymatic conversion, 18 phenylamine-incorporated angucyclinone derivatives with halogen, methyl, methoxy, and carboxy substitutions were efficiently generated under mild conditions. These results highlighted the impressive roles of nonenzymatic reactions in expanding the structural diversity of angucyclinones.

Generation of Unusual Aromatic Polyketides by Incorporation of Phenylamine Analogues into a C-Ring-Cleaved Angucyclinone

“…Monosubstituted phenylamine analogues have been efficiently incorporated into 2 under mild conditions, previously [2]. To test the efficiency of other phenylamine analogues in the incorporation, we selected four analogues with distinct substitutions on the phenylamine.…”

“…The structures of these natural products feature a tetracyclic benz(a)anthracene skeleton, which can be modified by enzymatic or nonenzymatic reactions to achieve impressive structural diversity. As a part of our ongoing project for natural product discovery and biosynthesis from marine bacteria [2][3][4][5][6], we previously discovered an unusual phenylamine-incorporated angucyclinone (1) featuring 1phenylbenzo(cd)indol-3(1H)-one moiety from a marine Streptomyces sp. PKU-MA00218 [2].…”

“…As a part of our ongoing project for natural product discovery and biosynthesis from marine bacteria [2][3][4][5][6], we previously discovered an unusual phenylamine-incorporated angucyclinone (1) featuring 1phenylbenzo(cd)indol-3(1H)-one moiety from a marine Streptomyces sp. PKU-MA00218 [2]. Based on genome sequencing, bioinformatics analysis, heterologous expression, gene deletion, and nonenzymatic conversion in vitro, we identified that 1 was produced from the nonenzymatic conversion of a C-ring-cleaved angucyclinone (2) with phenylamine, and generated a series of derivatives by the incorporation of monosubstituted phenylamine analogues into 2.…”

“…PKU-MA00218 [2]. Based on genome sequencing, bioinformatics analysis, heterologous expression, gene deletion, and nonenzymatic conversion in vitro, we identified that 1 was produced from the nonenzymatic conversion of a C-ring-cleaved angucyclinone (2) with phenylamine, and generated a series of derivatives by the incorporation of monosubstituted phenylamine analogues into 2. These derivatives represented a new group of angucyclinones and showed different degrees of activation activities on nuclear factor erythroid 2-related factor 2 (Nrf2) transcriptions in HepG2 cells, highlighting the powerful combination of biosynthesis and nonenzymatic reactions in the generation of structurally unusual and bioactive molecules.…”

Antibacterial and Cytotoxic Bridged and Ring Cleavage Angucyclinones From a Marine Streptomyces sp

“…Angucyclines and angucyclinones (sugarless) represent the largest family of type II polyketide synthase (PKS)-engineered natural products (Rohr and Thiericke, 1992 ; Krohn and Rohr, 1997 ; Kharel et al, 2012 ), which share a characteristic tetracyclic benz[ a ]anthracene core and exhibit a wide range of biological activities (Shaaban et al, 2012 ; Ma et al, 2015 ; Xie et al, 2016 ; Yixizhuoma et al, 2017 ; Liu et al, 2019 ; Wu et al, 2019 ). Actinobacteria are the exclusive producers of angucyclines and angucyclinones that have been proven to be a prolific source of antibiotics for the production of 45% of all reported microbial active metabolites (Bérdy, 2005 ; Arens et al, 2013 ).…”