pgp - publications

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1. J Med Chem. 2012 Feb 9. [Epub ahead of print]

Amine linked Flavonoid Dimers as Modulators for P-glycoprotein-based Multidrug
Resistance: Structure-Activity Relationship and Mechanism of Modulation.

Chan KF, Wong IL, Kan JW, Yan CS, Chow LM, Chan TH.

Here we report a great improvement in reversal potency of cancer drug resistance
when flavonoid dimers possess functionally-substituted amino polyethylene 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 EC50
at nanomolar range, (2) low toxicity and high therapeutic index and (3)
preferentially inhibiting 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 plot suggest that 18 is a competitive
inhibitor to DOX in binding to P-gp with a Ki of 0.28-0.34 ┬ÁM and a Hill
coefficient of 1.17. Moreover, LCC6MDR cell displays about 2.1-fold lower
intracellular accumulation of 18 as compared to the wild type, suggesting that 18
is a P-gp substrate as well.

PMID: 22320402 [PubMed - as supplied by publisher]