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http://hdl.handle.net/10397/82038
| Title: | Alkyne-, azide- and triazole-containing flavonoids as modulators for multidrug resistance in cancers | Authors: | Chow, LMC Chan, TH Chan, KF Wong, ILK Law, MC |
Issue Date: | 19-Feb-2019 | Source: | US Patent 10,208,025 B2. Washington, DC: US Patent and Trademark Office, 2019. | Abstract: | A triazole bridged flavonoid dimer compound library was efficiently constructed via the cycloaddition reaction of a series of flavonoid-containing azides (Az 1-15) and alkynes (Ac 1-17). These triazole bridged flavonoid dimers and their precursor alkyne- and azide-containing flavonoids were screened for their ability to modulate multidrug resistance (MDR) in P-gp-overexpressed cell line (LCC6MDR), MRP1-overexpressed cell line (2008/MRP1) and BCRP-overexpressed cell line (HEK293/R2 and MCF7-MX100). Generally, they displayed very promising MDR reversal activity against P-gp-, MRP1- and BCRP-mediated drug resistance. Moreover, they showed different levels of selectivity for various transporters. Overall, they can be divided into mono-selective, dual-selective and multi-selective modulators for the P-gp, MRP1 and BCRP transporters. The EC.sub.50 values for reversing paclitaxel resistance (141-340 nM) of LCC6MDR cells, DOX (78-590 nM) and vincristine (82-550 nM) resistance of 2008/MRP1 cells and topotecan resistance (0.9-135 nM) of HEK293/R2 and MCF7-MX100 cells were at nanomolar range. Importantly, a number of compounds displayed EC.sub.50 at or below 10 nM in BCRP-overexpressed cell lines, indicating that these bivalent triazoles more selectively inhibit BCRP transporter than the P-gp and MRP1 transporters. Most of the dimers are notably safe MDR chemosensitizers as indicated by their high therapeutic index values. | Rights: | Assignee: The Hong Kong Polytechnic University Assignee: The Royal Institution for the Advancement of Learning/McGill University |
| Appears in Collections: | Patent |
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| us10208025b2.pdf | 5.73 MB | Adobe PDF | View/Open |
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