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)
- Author(s)
- Theresa Schwarz, Floriane Montanari, Anna Cseke, Katrin Wlcek, Lene Visvader, Sarah Palme, Peter Chiba, Karl Kuchler, Ernst Urban, Gerhard Ecker
- 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.
- Organisation(s)
- Department of Biochemistry and Cell Biology
- External organisation(s)
- Universität Wien, Medizinische Universität Wien
- Journal
- ChemMedChem: chemistry enabling drug discovery
- Volume
- 11
- Pages
- 1380-1394
- No. of pages
- 15
- ISSN
- 1860-7179
- DOI
- https://doi.org/10.1002/cmdc.201500592
- Publication date
- 03-2016
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104015 Organic chemistry
- Keywords
- ASJC Scopus subject areas
- Drug Discovery, Molecular Medicine, Biochemistry, Pharmacology, Toxicology and Pharmaceutics(all), Pharmacology, Organic Chemistry
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucris.univie.ac.at/portal/en/publications/subtle-structural-differences-trigger-inhibitory-activity-of-propafenone-analogues-at-the-two-polyspecific-abc-transporters-pglycoprotein-pgp-and-breast-cancer-resistance-protein-bcrp(355403ed-e6af-48b9-831e-eab18a32d803).html