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

Hua Xiao,Juan Song,Guiyang Wang,Jing Jin,Yi Kuang,Donghui Yang,Zhengdong Wang,Min Ye,Ming Ma

doi:10.3390/molecules26071959

Abstract

Angucyclinones are aromatic polyketides that possess impressive structural diversity and significant biological activities. The structural diversity of these natural products is attributed to various enzymatic or nonenzymatic modifications on their tetracyclic benz(a)anthracene skeleton. Previously, we discovered an unusual phenylamine-incorporated angucyclinone (1) from a marine Streptomyces sp. PKU-MA00218, and identified that it was produced from the nonenzymatic conversion of a C-ring-cleaved angucyclinone (2) with phenylamine. In this study, we tested the nonenzymatic conversion of 2 with more phenylamine analogues, to expand the utility of this feasible conversion in unusual angucyclinones generation. The (3-ethynyl)phenylamine and disubstituted analogues including (3,4-dimethyl)phenylamine, (3,4-methylenedioxy)phenylamine, and (4-bromo-3-methyl)phenylamine were used in the conversion of 2, which was isolated from the fermentation of Streptomyces sp. PKU-MA00218. All four phenylamine analogues were incorporated into 2 efficiently under mild conditions, generating new compounds 3–6. The activation of 3–6 on nuclear factor erythroid 2-related factor 2 (Nrf2) transcription were tested, which showed that 4 possessing a dimethyl-substitution gave most potent activity. These results evidenced that disubstitutions on phenylamine can be roughly tolerated in the nonenzymatic reactions with 2, suggesting extended applications of more disubstituted phenylamines incorporation to generate new bioactive angucyclinones in the future.

Highlights

Angucyclinones are aromatic polyketides produced by type II polyketide synthases (PKSs) from actinomycetes exclusively [1]
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
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

Summary

Introduction

Angucyclinones are aromatic polyketides produced by type II polyketide synthases (PKSs) from actinomycetes exclusively [1]. 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. The generation of 3–6 can be efficiently achieved under mild conditions, and the activation of 3–6 on Nrf transcriptions were subsequently tested

Methods

Results

Conclusion