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Potent and Selective Inhibitors of Breast Cancer Resistance Protein (ABCG2) Derived from the p-Glycoprotein (ABCB1) Modulator Tariquidar

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Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, and Institute of Organic Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer Feld 366, D-69120 Heidelberg, Germany
* To whom correspondence should be addressed. Phone: +49-941 9434827. Fax: +49-941 9434820. E-mail: [email protected]
†Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg.
‡Institute of Organic Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg.
§Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg.
Cite this: J. Med. Chem. 2009, 52, 4, 1190–1197
Publication Date (Web):January 26, 2009
https://doi.org/10.1021/jm8013822
Copyright © 2009 American Chemical Society

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    Abstract

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    The efflux pumps ABCB1 (p-gp, MDR1) and ABCG2 (BCRP) are expressed to a high extent by endothelial cells at the blood−brain barrier (BBB) and other barrier tissues and are involved in drug resistance of tumor (stem) cells. Whereas numerous ABCB1 inhibitors are known, only a few ABCG2 modulators with submicromolar activity have been published. Starting from tariquidar (4) analogues as ABCB1 modulators, minimal structural modifications resulted in a drastic shift in favor of ABCG2 inhibition. Highest potency was found when the 3,4-dimethoxy-2-(quinoline-3-carbonylamino)benzoyl moiety in 4 was replaced with a 4-methoxycarbonylbenzoyl moiety bearing a hetarylcarboxamido group in 3-position, e.g., quinoline-3-carboxamido (5, IC50: 119 nM) or quinoline-2-carboxamido (6, IC50: 60 nM, flow cytometric mitoxantrone efflux assay, topotecan-resistant MCF-7 breast cancer cells); the selectivity for ABCG2 over ABCB1 was about 100−500 fold and the compounds were inactive at ABCC2 (MRP2). Chemosensitivity assays against MCF-7/Topo cells revealed that the nontoxic inhibitor 6 completely reverted ABCG2-mediated topotecan resistance at concentrations >100 nM, whereas 5 showed ABCG2 independent cytotoxicity. ABCG2 inhibitors might be useful for cancer treatment with respect to reversal of multidrug resistance, overcoming the BBB and targeting of tumor stem cells.

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    Experimental details and analytical data for the intermediates 16d, 18ae, 19ae and for the target compounds 5, 715, 1H- and 13C NMR spectra and HPLC analysis including tracings of key target compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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