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http://hdl.handle.net/10397/95467
Title: | Flavonoid monomers as potent, nontoxic, and selective modulators of the breast cancer resistance protein (ABCG2) | Authors: | Wong, ILK Zhu, X Chan, KF Liu, Z Chan, CF Chow, TS Chong, TC Law, MC Cui, J Chow, LMC Chan, TH |
Issue Date: | 14-Oct-2021 | Source: | Journal of medicinal chemistry, 14 Oct. 2021, v. 64, no. 19, p. 14311-14331 | Abstract: | We synthesize various substituted triazole-containing flavonoids and identify potent, nontoxic, and highly selective BCRP inhibitors. Ac18Az8, Ac32Az19, and Ac36Az9 possess m-methoxycarbonylbenzyloxy substitution at C-3 of the flavone moiety and substituted triazole at C-4′ of the B-ring. They show low toxicity (IC50 toward L929 > 100 μM), potent BCRP-inhibitory activity (EC50 = 1-15 nM), and high BCRP selectivity (BCRP selectivity over MRP1 and P-gp > 67-714). They inhibit the efflux activity of BCRP, elevate the intracellular drug accumulation, and restore the drug sensitivity of BCRP-overexpressing cells. Like Ko143, Ac32Az19 remarkably exhibits a 100% 5D3 shift, indicating that it can bind and cause a conformational change of BCRP. Moreover, it significantly reduces the abundance of functional BCRP dimers/oligomers by half to retain more mitoxantrone in the BCRP-overexpressing cell line and that may account for its inhibitory activity. They are promising candidates to be developed into combination therapy to overcome MDR cancers with BCRP overexpression. | Publisher: | American Chemical Society | Journal: | Journal of medicinal chemistry | ISSN: | 0022-2623 | EISSN: | 1520-4804 | DOI: | 10.1021/acs.jmedchem.1c00779 | Rights: | © 2021 American Chemical Society This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.1c00779. |
Appears in Collections: | Journal/Magazine Article |
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Wong_Flavonoid_Monomers_As.pdf | Pre-Published version | 2.57 MB | Adobe PDF | View/Open |
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