Cytotoxic and antibacterial polyketide-indole hybrids synthesized from indole-3-carbinol by Daldinia eschscholzii

作     者：Liping Lin Nan Jiang Huimin Wu Yaning Mei Jie Yang Renxiang Tan 

作者机构：State Key Laboratory Cultivation Base for TCM Quality and Efficacy Nanjing University of Chinese Medicine State Key Laboratory of Pharmaceutical Biotechnology Nanjing University School of Pharmacy Nanjing Medical University Department of Clinical Laboratory the First Affiliated Hospital of Nanjing Medical University Jiangsu Province Academy of Traditional Chinese Medicine 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2019年第9卷第2期

页      面：369-380页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 100701[医学-药物化学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(Grant Nos.81530089,21661140001,21672101,and 81503232) National Key R&D Program of China(2018YFC1706200) the Drug Innovation Major Project(2018ZX09711-001-007-004,China)for generous support 

主　　题：Polyketide-indole hybrids Indole-3-carbinol Daldinia eschscholzii 8-Amino-7-oxononanoate synthase Decarboxylative Claisen condensation Antibacterial Anticancer 

摘      要：Two skeletally undescribed polyketide-indole hybrids(PIHs), named indolchromins A and B,were generated from indole-3-carbinol(I3 C) in the fungal culture(Daldinia eschscholzii). The indolchromin structures were elucidated mainly by their 1 D and 2 D NMR spectra with the former confirmed by the single-crystal X-ray crystallographic analysis. Each indolchromin alkaloid was chirally separated into four isomers, whose absolute configurations were assigned by comparing the recorded circular dichroism(CD) spectra with the electronic CD(ECD) curves computed for all optional stereoisomers. Furthermore, the indolchromin construction pathways in fungal culture were clarified through enzyme inhibition, precursor feeding experiment, and energy calculation. The cascade reactions,including decarboxylative Claisen condensation catalyzed by 8-amino-7-oxononanoate synthase(AONS),C(sp3)-H activation, double bond migration, and Michael addition, all undergone compatibly during the fungal cultivation. In an MIC range of 1.3–8.6 μmol/L,(2 S,4 R)-and(2 R,4 S)-indolchromin A and(2 R,4 S)-indolchromin B are inhibitory against Clostridium perfringens, Clostridium difficile, Veillonella sp.,Bacteroides fragilis, and Streptococcus pyogenes.(2 R,4 S)-Indolchromin A and(2 S,4 S)-indolchromin B were cytotoxic against the human breast cancer cell line MDA-MB-231 with IC50 values of 27.9 and131.2 nmol/L, respectively, with the former additionally active against another human breast cancer cell line MCF-7(IC_(50)94.4 nmol/L).