Kühnle, Matthias and Egger, Michael and Müller, Christine and Mahringer, Anne and Bernhardt, Günther and Fricker, Gert and König, Burkhard and Buschauer, Armin (2009) Potent and selective inhibitors of breast cancer resistance protein (ABCG2) derived from the p-glycoprotein (ABCB1) modulator tariquidar. Journal of Medicinal Chemistry 52 (4), pp. 1190-1197.
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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) analogs 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; the compounds were inactive at ABCC2 (MRP2). Chemosensitivity assays against MCF-7/Topo cells revealed that the non-toxic 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.
|Date:||26 January 2009|
|Institutions:|| Chemistry and Pharmacy > Institut für Organische Chemie > Lehrstuhl Prof. Dr. Burkhard König|
Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer)
|Projects:||GRK 760, Graduiertenkolleg Medizinische Chemie|
|Keywords:||ABC transporter, BCRP, ABCG2, p-glycoprotein, ABCB1, cytotoxicity, MCF-7 breast cancer cells|
|Subjects:||500 Science > 570 Life sciences|
500 Science > 540 Chemistry & allied sciences
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Yes|
|Deposited On:||14 Jan 2009 11:03|
|Last Modified:||08 Nov 2010 10:18|