Tetrahydroquinoline/4,5-Dihydroisoxazole Molecular Hybrids as Inhibitors of Breast Cancer Resistance Protein (BCRP/ABCG2).

Autor: Vesga LC; Faculty of Health Sciences, University of Eastern Finland, Kuopio, 70211, Finland.; Escuela de Química, Universidad Industrial de Santander, A. A. 678, Bucaramanga, Colombia.; Grupo de Investigación en Compuestos Orgánicos de Interés Medicinal CODEIM, Universidad Industrial de Santander, A. A. 678, Piedecuesta, Colombia., Kronenberger T; Faculty of Health Sciences, University of Eastern Finland, Kuopio, 70211, Finland.; Department of Medical Oncology and Pneumology, Internal Medicine VIII, University Hospital of Tübingen, Otfried-Müller-Strasse 14, 72076, Tübingen, Germany., Tonduru AK; Faculty of Health Sciences, University of Eastern Finland, Kuopio, 70211, Finland., Kita DH; Laboratory of Cancer Drug Resistance, Federal University of Paraná, PR 80210-170, Curitiba, Brazil.; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Zattoni IF; Laboratory of Cancer Drug Resistance, Federal University of Paraná, PR 80210-170, Curitiba, Brazil., Bernal CC; Grupo de Investigación en Compuestos Orgánicos de Interés Medicinal CODEIM, Universidad Industrial de Santander, A. A. 678, Piedecuesta, Colombia., Bohórquez ARR; Grupo de Investigación en Compuestos Orgánicos de Interés Medicinal CODEIM, Universidad Industrial de Santander, A. A. 678, Piedecuesta, Colombia., Mendez-Sánchez SC; Escuela de Química, Universidad Industrial de Santander, A. A. 678, Bucaramanga, Colombia.; Grupo de Investigación en Compuestos Orgánicos de Interés Medicinal CODEIM, Universidad Industrial de Santander, A. A. 678, Piedecuesta, Colombia., Ambudkar SV; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Valdameri G; Laboratory of Cancer Drug Resistance, Federal University of Paraná, PR 80210-170, Curitiba, Brazil., Poso A; Faculty of Health Sciences, University of Eastern Finland, Kuopio, 70211, Finland.; Department of Medical Oncology and Pneumology, Internal Medicine VIII, University Hospital of Tübingen, Otfried-Müller-Strasse 14, 72076, Tübingen, Germany.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2021 Sep 06; Vol. 16 (17), pp. 2686-2694. Date of Electronic Publication: 2021 May 18.
DOI: 10.1002/cmdc.202100188
Abstrakt: Multidrug resistance (MDR) is one of the major factors in the failure of many chemotherapy approaches. In cancer cells, MDR is mainly associated with the expression of ABC transporters such as P-glycoprotein, MRP1 and ABCG2. Despite major efforts to develop new selective and potent inhibitors of ABC drug transporters, no ABCG2-specific inhibitors for clinical use are yet available. Here, we report the evaluation of sixteen tetrahydroquinoline/4,5-dihydroisoxazole derivatives as a new class of ABCG2 inhibitors. The affinity of the five best inhibitors was further investigated by the vanadate-sensitive ATPase assay. Molecular modelling data, proposing a potential binding mode, suggest that they can inhibit the ABCG2 activity by binding on site S1, previously reported as inhibitors binding region, as well targeting site S2, a selective region for substrates, and by specifically interacting with residues Asn436, Gln398, and Leu555. Altogether, this study provided new insights into THQ/4,5-dihydroisoxazole molecular hybrids, generating great potential for the development of novel most potent ABCG2 inhibitors.
(© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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