Cytotoxic and Antibacterial Polyketide-Indole Hybrids Synthesized From indole-3-carbinol by Daldinia eschscholzii

Acta Pharm Sin B. 2019 Mar;9(2):369-380. doi: 10.1016/j.apsb.2018.09.011. Epub 2018 Sep 28.

Abstract

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(sp 3)-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).

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