期刊
ORGANIC & BIOMOLECULAR CHEMISTRY
卷 13, 期 19, 页码 5424-5431出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5ob00246j
关键词
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资金
- CSIR Innovation center [ITR001]
- CSIR 12th FYP project [BSC-0205]
Polysubstituted pyrrole natural products, lamellarins, are known to overcome multi-drug resistance in cancer via the inhibition of p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux pumps. Herein, a series of simplified polysubstituted pyrroles, prepared via a one-pot domino protocol, were screened for P-gp inhibition in P-gp overexpressing human adenocarcinoma LS-180 cells using a rhodamine 123 efflux assay. Several compounds showed the significant inhibition of P-gp at 50 mu M, as indicated by increase in the intracellular accumulation of Rh123 in LS-180 cells. Furthermore, pyrrole 5i decreased the efflux of digoxin, a FDA approved P-gp substrate in MDCK-MDR1 cells with an IC50 of 11.2 mu M. In in vivo studies, following the oral administration of a P-gp substrate drug, rifampicin, along with compound 5i, the C-max and AUC(0-infinity) of rifampicin was enhanced by 31% and 46%, respectively. All the compounds were then screened for their ability to potentiate ciprofloxacin activity via the inhibition of Staphylococcus aureus Nor A efflux pump. Pyrrole 5i showed the significant inhibition of S. aureus Nor A efflux pump with 8-and 4-fold reductions in the MIC of ciprofloxacin at 50 and 6.25 mu M, respectively. The molecular docking studies of compound 5i with the human P-gp and S. aureus Nor A efflux pump identified its plausible binding site and key interactions. Thus, the results presented herein strongly indicate the potential of this scaffold for its use as multi-drug resistance reversal agent or bioavailability enhancer.
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