Piperazinobenzopyranones and Phenalkylaminobenzopyranones: Potent Inhibitors of Breast Cancer Resistance Protein (ABCG2) - EPHE - École pratique des hautes études
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2005

Piperazinobenzopyranones and Phenalkylaminobenzopyranones: Potent Inhibitors of Breast Cancer Resistance Protein (ABCG2)

Piperazinobenzopyranones and phenalkylaminobenzopyranones: potent inhibitors of breast cancer resistance protein (ABCG2).

Bastien Gerby
Madeleine Blanc
  • Fonction : Auteur
Xavier Ronot
  • Fonction : Auteur
  • PersonId : 953072
Jean Boutonnat

Résumé

In continuing research that led us to identify chromanone derivatives (J. Med. Chem. 2003, 46, 2125) as P-glycoprotein inhibitors, we obtained analogues able to modulate multidrug resistance (MDR) mediated by the breast cancer resistance protein (BCRP). The linkage of 5-hydroxybenzopyran-4-one to piperazines or phenalkylamines affords highly potent inhibitors of BCRP. By using sensitive (HCT116) and resistant colon cancer cells expressing BCRP, we evaluated the effect of 14 benzopyranone (chromone) derivatives on the accumulation and the cytotoxic effect of the anticancer drug, mitoxantrone. At 10 microM, three compounds increased both intracellular accumulation and cytotoxicity of mitoxantrone in HCT116/R cells with a comparable rate as fumitremorgin C and Gleevec used as reference inhibitors. The most potent molecules 5b and 5c are still active at 1 microM, whereas FTC shows weak inhibition. These molecules do not induce cell death as shown by the cell cycle distribution study, which makes them potential candidates for in vivo studies.

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Ahcene Boumendjel, Edwige Nicolle, Thomas Moraux, Bastien Gerby, Madeleine Blanc, et al.. Piperazinobenzopyranones and Phenalkylaminobenzopyranones: Potent Inhibitors of Breast Cancer Resistance Protein (ABCG2). Journal of Medicinal Chemistry, 2005, 48 (23), pp.7275-7281. ⟨10.1021/jm050705h⟩. ⟨hal-02353671⟩
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