Stereoselective Modulation of P-Glycoprotein by Chiral Small Molecules

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Abstract

Inhibition of drug efflux pumps such as P-glycoprotein (P-gp) is an approach toward combating multidrug resistance, which is a significant hurdle in current cancer treatments. To address this, N-substituted aryloxymethyl pyrrolidines were designed and synthesized in their homochiral forms in order to investigate the stereochemical requirements for the binding site of Pgp. Our study provides evidence that the chiral property of molecules could be a strategy for improving the capacity for interacting with P-gp, as the most active compounds of the series stereoselectively modulated this efflux pump. The naphthalene- 1-yl analogue (R)-2-[(2,3-dichlorophenoxy)methyl]-1- (naphthalen-1-ylmethyl)pyrrolidine) [(R)-7a] emerged foremost for its potency and stereoselectivity toward P-gp, with the S enantiomer being nearly inactive. The modulation of P-gp by (R)-7a involved consumption of ATP, thus demonstrating that the compound behaves as a P-gp substrate.

Autore Pugliese

Tutti gli autori

  • CAROCCI A.;CATALANO A.;LOVECE A.;FRANCHINI C.;BRUNO C.;LENTINI G.;PERRONE M.G.;CAVALLUZZI M.M.;CONTINO M.;COLABUFO N.A.

Titolo volume/Rivista

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Anno di pubblicazione

2016

ISSN

1860-7179

ISBN

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Numero di citazioni Wos

Nessuna citazione

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Numero di citazioni Scopus

3

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Settori ERC

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Codici ASJC

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