Amine linked flavonoid dimers as modulators for P-glycoprotein-based multidrug resistance: structure-activity relationship and mechanism of modulation

Kin-Fai Chan; Iris L K Wong; Jason W Y Kan; Clare S W Yan; Larry M C Chow; Tak Hang Chan

doi:10.1021/jm201121b

Amine linked flavonoid dimers as modulators for P-glycoprotein-based multidrug resistance: structure-activity relationship and mechanism of modulation

J Med Chem. 2012 Mar 8;55(5):1999-2014. doi: 10.1021/jm201121b. Epub 2012 Feb 22.

Authors

Kin-Fai Chan¹, Iris L K Wong, Jason W Y Kan, Clare S W Yan, Larry M C Chow, Tak Hang Chan

Affiliation

¹ Department of Applied Biology and Chemical Technology, State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hong Kong SAR, China.

PMID: 22320402
DOI: 10.1021/jm201121b

Abstract

Here we report a great improvement in reversal potency of cancer drug resistance when flavonoid dimers possess a functionally substituted aminopolyethylene glycol linker. The most potent compound, 18, contains a N-benzyl group at the linker. It has many advantages including (1) high potencies in reversing P-glycoprotein (P-gp) mediated resistance in LCC6MDR cells to various anticancer drugs with EC(50) in the nanomolar range, (2) low toxicity and high therapeutic index, and (3) preferential inhibition of P-gp over multidrug resistance protein 1 and breast cancer resistance protein. Compound 18 stimulates P-gp-ATPase activity by 2.7-fold and mediates a dose-dependent inhibition of doxorubicin (DOX) transport activity. Lineweaver-Burk and Dixon plots suggest that 18 is a competitive inhibitor to DOX in binding to P-gp with a K(i) of 0.28-0.34 μM and a Hill coefficient of 1.17. Moreover, the LCC6MDR cell displays about 2.1-fold lower intracellular accumulation of 18 compared to the wild type, suggesting that 18 is a P-gp substrate as well.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters / antagonists & inhibitors
Adenosine Triphosphatases / antagonists & inhibitors
Amines / chemical synthesis*
Amines / chemistry
Amines / pharmacology
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Benzylamines / chemical synthesis*
Benzylamines / chemistry
Benzylamines / pharmacology
Cell Line, Tumor
Dimerization
Doxorubicin / metabolism
Doxorubicin / pharmacology
Drug Resistance, Multiple / drug effects*
Drug Resistance, Neoplasm / drug effects*
Drug Screening Assays, Antitumor
Flavones / chemical synthesis*
Flavones / chemistry
Flavones / pharmacology
Flavonoids / chemical synthesis*
Flavonoids / chemistry
Flavonoids / pharmacology
Humans
Multidrug Resistance-Associated Proteins / antagonists & inhibitors
Neoplasm Proteins / antagonists & inhibitors
Paclitaxel / pharmacology
Polyethylene Glycols / chemical synthesis*
Polyethylene Glycols / chemistry
Polyethylene Glycols / pharmacology
Solubility
Structure-Activity Relationship

Substances

1,13-bis(4'-(4H-chromen-4-on-2-yl)phenyl)-N-(benzyl)-1,4,10,13-tetraoxa-7-azatridecane
ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
Amines
Antineoplastic Agents
Benzylamines
Flavones
Flavonoids
Multidrug Resistance-Associated Proteins
Neoplasm Proteins
Polyethylene Glycols
Doxorubicin
Adenosine Triphosphatases
Paclitaxel
multidrug resistance-associated protein 1