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Stereoselective Modulation of P‐Glycoprotein by Chiral Small Molecules |
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| Authors: | Dr Alessia Carocci Dr Alessia Catalano Dr Francesco Turi Dr Angelo Lovece Dr Maria M Cavalluzzi Dr Claudio Bruno Prof Nicola A Colabufo Dr Marialessandra Contino Dr Maria G Perrone Prof Carlo Franchini Prof Giovanni Lentini |
| Affiliation: | Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Bari, Italy |
| 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. |
| Keywords: | aryloxymethyl pyrrolidines drug efflux multidrug resistance P-glycoprotein stereoselectivity |
