Amine linked flavonoid dimers as modulators for P-glycoprotein-based multidrug resistance: structure-activity relationship and mechanism of modulation
| Autor: | Kin-Fai Chan, Jason W. Y. Kan, Iris L. K. Wong, Tak Hang Chan, Larry M.C. Chow, Clare S. W. Yan |
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| Rok vydání: | 2012 |
| Předmět: |
Benzylamines
Abcg2 Paclitaxel Antineoplastic Agents Polyethylene Glycols Structure-Activity Relationship Multidrug Resistance Protein 1 Cell Line Tumor Drug Discovery Structure–activity relationship ATP Binding Cassette Transporter Subfamily G Member 2 Humans ATP Binding Cassette Transporter Subfamily B Member 1 Amines P-glycoprotein Adenosine Triphosphatases Flavonoids biology Chemistry Wild type Flavones Drug Resistance Multiple Neoplasm Proteins Multiple drug resistance Biochemistry Solubility Doxorubicin Drug Resistance Neoplasm biology.protein Molecular Medicine ATP-Binding Cassette Transporters Drug Screening Assays Antitumor Multidrug Resistance-Associated Proteins Linker Dimerization |
| Zdroj: | Journal of medicinal chemistry. 55(5) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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