Original Articles
Liping Lin, Nan Jiang, Huimin Wu, Yaning Mei, Jie Yang, Renxiang Tan. Cytotoxic and antibacterial polyketide-indole hybrids synthesized from indole-3-carbinol by Daldinia eschscholzii[J]. Acta Pharmaceutica Sinica B, 2019, 9(2): 369-380

Cytotoxic and antibacterial polyketide-indole hybrids synthesized from indole-3-carbinol by Daldinia eschscholzii
Liping Lina,b, Nan Jiangc, Huimin Wub, Yaning Meid, Jie Yange, Renxiang Tana,b
a State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing 210046, China;
b State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023 China;
c School of Pharmacy, Nanjing Medical University, Nanjing 210029, China;
d Department of Clinical Laboratory, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China;
e Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China
Two skeletally undescribed polyketide-indole hybrids (PIHs), named indolchromins A and B, were generated from indole-3-carbinol (I3C) in the fungal culture (Daldinia eschscholzii). The indolchromin structures were elucidated mainly by their 1D and 2D 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, (2S,4R)-and (2R,4S)-indolchromin A and (2R,4S)-indolchromin B are inhibitory against Clostridium perfringens, Clostridium difficile, Veillonella sp., Bacteroides fragilis, and Streptococcus pyogenes. (2R,4S)-Indolchromin A and (2S,4S)-indolchromin B were cytotoxic against the human breast cancer cell line MDA-MB-231 with IC50 values of 27.9 and 131.2 nmol/L, respectively, with the former additionally active against another human breast cancer cell line MCF-7 (IC50 94.4 nmol/L).
Key words:    Polyketide-indole hybrids    Indole-3-carbinol    Daldinia eschscholzii    8-Amino-7-oxononanoate synthase    Decarboxylative Claisen condensation    Antibacterial    Anticancer   
Received: 2018-07-10     Revised: 2018-08-25
DOI: 10.1016/j.apsb.2018.09.011
Funds: This project was successively supported by the National Natural Science Foundation of China (Grant Nos.81530089,21661140001,21672101,and 81503232).We also thank National Key R&D Program of China (2018YFC1706200) and the Drug Innovation Major Project (2018ZX09711-001-007-004,China) for generous support.
Corresponding author: Renxiang Tan     Email:rxtan@nju.edu.cn
Author description:
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Liping Lin
Nan Jiang
Huimin Wu
Yaning Mei
Jie Yang
Renxiang Tan

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