title: Subtle Structural Differences Trigger Inhibitory Activity of Propafenone Analogues at the Two Polyspecific ABC Transporters: P-Glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).
abstract: The transmembrane ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are widely recognized for their role in cancer multidrug resistance and absorption and distribution of compounds. Furthermore, they are linked to drug-drug interactions and toxicity. Nevertheless, due to their polyspecificity, a molecular understanding of the ligand-transporter interaction, which allows designing of both selective and dual inhibitors, is still in its infancy. This study comprises a combined approach of synthesis, in silico prediction, and in vitro testing to identify molecular features triggering transporter selectivity. Synthesis and testing of a series of 15 propafenone analogues with varied rigidity and basicity of substituents provide first trends for selective and dual inhibitors. Results indicate that both the flexibility of the substituent at the nitrogen atom, as well as the basicity of the nitrogen atom, trigger transporter selectivity. Furthermore, inhibitory activity of compounds at P-gp seems to be much more influenced by logP than those at BCRP. Exploiting these differences further should thus allow designing specific inhibitors for these two polyspecific ABC-transporters.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090, Vienna, Austria.
authors.forename: Theresa
authors.identifier: 0000-0002-1845-3521
authors.initials: T
authors.lastname: Schwarz
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090, Vienna, Austria.
authors.forename: Floriane
authors.identifier: 0000-0002-4676-6170
authors.initials: F
authors.lastname: Montanari
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090, Vienna, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Cseke
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090, Vienna, Austria.
authors.forename: Katrin
authors.initials: K
authors.lastname: Wlcek
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090, Vienna, Austria.
authors.forename: Lene
authors.initials: L
authors.lastname: Visvader
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090, Vienna, Austria.
authors.forename: Sarah
authors.initials: S
authors.lastname: Palme
authors.affiliation: Department of Medicinal Chemistry, Medical University Vienna, Währingerstraße 10, 1090, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Chiba
authors.affiliation: Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University Vienna, Dr. Bohr-Gasse 9/2, 1030, Vienna, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Kuchler
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090, Vienna, Austria.
authors.forename: Ernst
authors.initials: E
authors.lastname: Urban
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090, Vienna, Austria. gerhard.f.ecker@univie.ac.at.
authors.forename: Gerhard F
authors.identifier: 0000-0003-4209-6883
authors.initials: GF
authors.lastname: Ecker
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D009363:Neoplasm Proteins / Q000378:metabolism*; D011405:Propafenone / Q000031:analogs & derivatives / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D011405:Propafenone
keywords: breast cancer resistance protein; inhibitor; p-glycoprotein; polypharmacology; propafenone