Stereoselective Modulation of P‐Glycoprotein by Chiral Small Molecules. Issue 1 (10th November 2015) - Carocci, Alessia
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. Abstract : Getting selective : A series of chiral N‐substituted aryloxymethyl pyrrolidines was investigated to determine the stereochemical requirements for the P‐glycoprotein (P‐gp) binding site. The presence of a naphthalen‐1‐yl substituent proved to be an important structural feature for activity toward P‐gp, with one of the naphthalen‐1‐yl analogues emerging as being particularly potent and stereoselective.