title: 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.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona n. 4, 70125, Bari, Italy. alessia.carocci@uniba.it.
authors.forename: Alessia
authors.initials: A
authors.lastname: Carocci
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona n. 4, 70125, Bari, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Catalano
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona n. 4, 70125, Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Turi
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona n. 4, 70125, Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Lovece
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona n. 4, 70125, Bari, Italy.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Cavalluzzi
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona n. 4, 70125, Bari, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bruno
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona n. 4, 70125, Bari, Italy.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona n. 4, 70125, Bari, Italy.
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona n. 4, 70125, Bari, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Perrone
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona n. 4, 70125, Bari, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Franchini
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona n. 4, 70125, Bari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lentini
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011759:Pyrrolidines; D054852:Small Molecule Libraries
keywords: P-glycoprotein; aryloxymethyl pyrrolidines; drug efflux; multidrug resistance; stereoselectivity