Alkyne-, azide- and triazole-containing flavonoids as modulators for multidrug resistance in cancers

Patent metadata

Field	Value
Publication number	US-9611256-B2
Application number	US-201314378869-A
Country	US
Kind code	B2
Filing date	Mar 1, 2013
Priority date	Mar 1, 2012
Publication date	Apr 4, 2017
Grant date	Apr 4, 2017

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 EC50 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 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 MRP1 transporters. Most of the dimers are notably safe MDR chemosensitizers as indicated by their high therapeutic index values.

First claim

The invention claimed is:

1. A compound of formula I:
flavonoid A-linker-(flavonoid B) n   I

wherein
flavonoid A is selected from the group consisting of chalcone, flavone, flavonol, flavanone, anthocyanin, and isoflavonoid;
each flavonoid B is selected from the group consisting of flavone, flavonol, flavanone, anthocyanin, and isoflavonoid;
n is 1 or 2; and
the linker is a group having at least one triazole bridged unit.

2. The compound of claim 1 , wherein the linker has 1 to 10 triazole bridged unit.

3. The compound of claim 2 , wherein the linker has 1 to 5 triazole bridged unit.

4. The compound of claim 3 , wherein the linker has 1 to 3 triazole bridged unit.

5. The compound of claim 1 , wherein the at least one triazole bridged unit further comprises at least one polyethylene glycol unit.

6. A compound of formula I:
flavonoid A-linker-(flavonoid B) n   I

wherein
flavonoid A is selected from the group consisting of flavone, flavonol, flavanone, anthocyanin, and isoflavonoid;
each flavonoid B is selected from the group consisting of chalcone, flavone, flavonol, flavanone, anthocyanin, and isoflavonoid
n is 1 or 2; and
the linker is a group having at least one triazole bridged unit.

7. The compound of claim 6 , wherein the linker has 1 to 10 triazole bridged unit.

8. The compound of claim 6 , wherein the at least one triazole bridged unit further comprises at least one polyethylene glycol unit.

9. A compound of formula I:
Flavonoid-linker-(flavonoid) n   I

wherein
the flavonoid is selected from the group consisting of chalcone, flavone, flavonol, flavanone, anthocyanin, and isoflavonoid;
n is 1 or 2; and
the linker is a group having at least one triazole bridged unit that further comprises at least one polyethylene glycol unit.

10. A method of reducing P-glycoprotein based multidrug resistance including the step of administering an effective amount of a compound of formula I as defined in claim 1 .

11. A method of reducing MRP 1-based multidrug resistance including the step of administering an effective amount of a compound of formula I as defined in claim 1 .

12. A method of reducing BCRP-based multidrug resistance including the step of administering an effective amount of a compound of formula I as defined in claim 1 .

13. A method of reducing resistance of a drug caused by overexpression of ABC transporters including the step of administering an effective amount of a compound of formula I as defined in claim 1 .

14. A method of treating drug-resistance cancers caused by overexpression of ABC transporters including the step of administering an effective amount of a compound of formula I as defined in claim 1 .

Assignees

• Univ Hong Kong Polytechnic
• Univ Mcgill

Inventors

• Chow Larry Ming Cheung
• Chan Tak Hang
• Chan Kin Fai
• Wong Iris Lai King
• Law Man Chun

Classifications

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D311/30

  not hydrogenated in the hetero ring, e.g. flavones · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title