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Benzoyl indoles with metabolic stability as reversal agents for ABCG2-mediated multidrug resistance.
- Source :
-
European Journal of Medicinal Chemistry . Oct2019, Vol. 179, p849-862. 14p. - Publication Year :
- 2019
-
Abstract
- Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI–H460/MX20 cells, and sensitized NCI–H460/MX20 cells to mitoxantrone. Mechanistic studies were conducted by [3H]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of anticancer drugs. Image 1 • We synthesized benzoyl indoles as reversal agents that reversed ABCG2-mediated MDR. • Benzoyl indoles could interact with the substrate-binding site of ABCG2. • Benzoyl indoles have synthetic tractability and enhanced metabolic stability compared to Ko143. • Anticancer drug in combination with benzoyl indoles could evade ABCG2-mediated MDR in cancer. [ABSTRACT FROM AUTHOR]
- Subjects :
- *MULTIDRUG resistance
*WESTERN immunoblotting
*INDOLE
*ADENOSINE triphosphate
Subjects
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 179
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 138342248
- Full Text :
- https://doi.org/10.1016/j.ejmech.2019.06.066