Structure-activity relationships of flavonoids as inhibitors of breast cancer resistance protein (BCRP).

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Pick A, Muller H, Mayer R, Haenisch B, Pajeva IK, Weigt M, Bonisch H, Muller CE, Wiese M

Structure-activity relationships of flavonoids as inhibitors of breast cancer resistance protein (BCRP).

Bioorg Med Chem. 2011 Mar 15;19(6):2090-102. doi: 10.1016/j.bmc.2010.12.043. Epub 2010 Dec 30.

PubMed ID
21354800 [ View in PubMed
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Abstract

Flavonoids are an interesting group of natural products ubiquitously present in human diet. Their consumption has been associated with various and differing beneficial health effects. However, several flavonoids have been reported to inhibit the breast cancer resistance protein (BCRP) encoded by the ABCG2 gene. Thus, the consumption of flavonoids with high inhibitory activity could change pharmacokinetics and drug levels of drugs that are BCRP substrates. In cancer patients receiving chemotherapy an increased intake of such flavonoids could lead to adverse effects. We investigated a structurally diverse set of flavonoids, including derivatives with a rare C-methylated structure that were isolated from plants used in traditional medicine. The flavones retusin and ayanin were found to be highly potent inhibitors of BCRP, showing only slightly less potency than Ko143, the most potent ABCG2 inhibitor known so far. The activity data were analyzed by 2D and 3D QSAR analyses and the results revealed the impact of the different substituents at the various positions of the flavonoid core on activity. Additionally, a lateral 2D QSAR analysis of data collected from the literature was performed aiming to derive more general information about the influence of distinct structural features on the inhibitory potency of flavonoids. The comparative QSAR analyses led to a consistent picture of the effects of the different substituents at various positions of the flavone backbone. The following structural features were found to contribute positively to BCRP inhibition: a hydroxyl group in position 5, double bond between position 2 and 3, and a methoxy group in position 3. The exchange of a 3-methoxy group by an OH-group acting also as a hydrogen bond donor, resulted in decrease in activity underlining the potential role of the hydrogen bond acceptor 3-OCH(3) for the interaction with BCRP.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
GenisteinATP-binding cassette sub-family G member 2IC 50 (nM)6900N/AN/ADetails
GenisteinATP-binding cassette sub-family G member 2IC 50 (nM)8800N/AN/ADetails
QuercetinATP-binding cassette sub-family G member 2IC 50 (nM)6900N/AN/ADetails
QuercetinATP-binding cassette sub-family G member 2IC 50 (nM)7600N/AN/ADetails
VerapamilP-glycoprotein 1IC 50 (nM)9800N/AN/ADetails