Stereoselective Modulation of P-Glycoprotein by Chiral Small Molecules.

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 P-gp. 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)-7 a] emerged foremost for its potency and stereoselectivity toward P-gp, with the S enantiomer being nearly inactive. The modulation of P-gp by (R)-7 a involved consumption of ATP, thus demonstrating that the compound behaves as a P-gp substrate.

• Authors: Alessia Carocci, Alessia Catalano, Francesco Turi, Angelo Lovece, Maria M Cavalluzzi, Claudio Bruno, Nicola A Colabufo, Marialessandra Contino, Maria G Perrone, Carlo Franchini, Giovanni Lentini
• Journal: ChemMedChem (ChemMedChem) Vol. 11 Issue 1 Pg. 93-101 (Jan 05 2016) ISSN: 1860-7187 [Electronic] Germany
• PMID: 26553253 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Pyrrolidines
• Small Molecule Libraries

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Dose-Response Relationship, Drug
• Humans
• Molecular Structure
• Pyrrolidines (chemical synthesis, chemistry, pharmacology)
• Small Molecule Libraries (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship