| Abstract
| - 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 multidrugresistance (MDR) mediated by the breast cancer resistance protein (BCRP). The linkage of5-hydroxybenzopyran-4-one to piperazines or phenalkylamines affords highly potent inhibitorsof BCRP. By using sensitive (HCT116) and resistant colon cancer cells expressing BCRP, weevaluated the effect of 14 benzopyranone (chromone) derivatives on the accumulation and thecytotoxic effect of the anticancer drug, mitoxantrone. At 10 μM, three compounds increasedboth intracellular accumulation and cytotoxicity of mitoxantrone in HCT116/R cells with acomparable rate as fumitremorgin C and Gleevec used as reference inhibitors. The most potentmolecules 5b and 5c are still active at 1 μM, whereas FTC shows weak inhibition. Thesemolecules do not induce cell death as shown by the cell cycle distribution study, which makesthem potential candidates for in vivo studies.
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