发明名称 |
ALKYNE-, AZIDE- AND TRIAZOLE-CONTAINING FLAVONOIDS AS MODULATORS FOR MULTIDRUG RESISTANCE IN CANCERS |
摘要 |
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-continaing flavonoids were screened for their ability to modulate multidrug resistance (MDR) in P-gp-overexpressed cell line (LCC6MDR), MRPl-overexpressed cell line (2008/MRPl) and BCRP-overexpressed cell line (HEK293/R2 and MCF7-MX100). Generally, they displayed very promising MDR reversal activity against P-gp-, MRPl- 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, MRPl and BCRP transporters. The EC50 values for reversing paclitaxel resistance (141 - 340 nM) of LCC6MDR cells, DOX (78 - 590 nM) and vincristine (82 - 550 nM) resistance of 2008/MRPl 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 EC50 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 MRPl transporters. Most of the dimers are notably safe MDR chemosensitizers as indicated by their high therapeutic index values. |
申请公布号 |
WO2013127361(A1) |
申请公布日期 |
2013.09.06 |
申请号 |
WO2013CN72058 |
申请日期 |
2013.03.01 |
申请人 |
THE HONG KONG POLYTECHNIC UNIVERSITY;MCGILL UNIVERSITY |
发明人 |
CHOW, LARRY MING CHEUNG;CHAN, TAK HANG;CHAN, KIN FAI;WONG, IRIS LAI KING;LAW, MAN CHUN |
分类号 |
C07D311/30;A61K31/35;A61K31/352;A61K31/365;A61P35/00;C07D249/04;C07D311/32 |
主分类号 |
C07D311/30 |
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