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

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, (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 IC 50 values of 27.9 and 131.2 nmol/L, respectively, with the former additionally active against another human breast cancer cell line MCF-7 (IC 50 94.4 nmol/L).

<p class="Author"> <p class="Title" style="text-indent:0mm;"> Natural Products from the genus <i>Daldinia</i> and Their Bioactivities

“…From the marine algicolous strain of D.eschscholzii, Tarman et al [8] obtained a new lactone helicascolide C (13, Figure 2). From medical plants, Shylaja et al [9] isolated D.eschscholtzii from Mussaenda luteola and purified compound 5-methoxy-2methyl-3-pentacosyl-1,4-benzoquinone (14). From the mangrove endophytic fungus D.eschscholtzii HJ001, Yang et al [10] obtained a new cytochalasin (15).…”

“…The observed potency was comparable to those of co-assayed streptomycin (MICs, 0.5-7.5 μmol/L) and tinidazole (MICs, 1.0-4.0 μmol/L). [14] Childinin B (63) exhibited remarkable activity against S. aureus subsp. aureus with an MIC90 value of 54.9 μg/mL (167.4 μM).…”

“…However, positive control drug doxorubicin with the IC50 values being 8.0 and 8.7 μmol/L against the MDA-MB-231 and MCF-7 cell lines, respectively. [14] Dalesindoloid A (31) displayed selective cytotoxicity against the HL-60 cell line with an IC50 value of 1.01 μM, and dalesindoloid B (32) showed discernible cytotoxicity against six of the seven cancer cell lines with an IC50 range of 7.44-14.64 μM. [13] 6,8-Dihydroxy-3-methyl-3,4-dihydroisocoumarin (40), (22R)hydroxylanosta-7,9(11),24-trien-3-one (41) and ergosterol (42) showed moderate cytotoxicity against four cancer cells, KB (a human epidermal carcinoma), MCF7 (human breast carcinoma), SK-LU-1 (human lung carcinoma) and HepG2 (hepatocellular carcinoma).…”

“…A-E (21-25), three new chromones, 7-hydroxy-5-methoxy-2,3-dimethylchromone (26), 5-methoxy-2-propylchromone (27), and 7-ethyl-8-hydroxy-6-methoxy-2,3-dimethylchromone (28), and two new lactones, helicascolides D and E (29-30).From the indole-3-carbinol exposed culture of D.eschscholzii, Lin et al[13] obtained two new alkaloids named dalesindoloids A (31) and B (32), shown in Figure3. And then, this group[14] found two skeletally undescribed polyketide-indole hybrids from the indole-3-carbinol-exposed culture of D. eschscholzii named indolchromins A and B (33-34). By replacement of the native promoter of the global regulator LaeA-like gene of D.eschscholzii by a strong gpdA promoter, Zhou et al[15] obtained two novel anti-inflammatory cyclopentenone metabolites named dalestones A and B (35-36).…”

Synthetic strategies, SAR studies, and computer modeling of indole 2 and 3-carboxamides as the strong enzyme inhibitors: a review

“…The presence of the carboxamide moiety at positions 2 and 3 has led to the activity of these compounds tend to inhibit various enzymes and proteins. Many studies have been done in this regard, and various properties such as anticancer [6], antimalarial [7], anti-inflammatory [8], anti-diabetic [9][10][11], antimicrobial [12], antitubercular [13], antibacterial [14] and cytotoxic [7] have been reported, for indole derivatives.…”