Deoxycholic acid derivatives as inhibitors of P-glycoprotein-mediated multidrug efflux

•Deoxycholic acid derivatives were identified as P-glycoprotein modulators.•All derivatives were evaluated through daunorubicin accumulation in K562/R7 cells.•All derivatives were evaluated through potentiation of doxorubicin in K562/R7 cells.•Intrinsic toxicity of all derivatives was evaluated on K562 cells.•Some deoxycholic acid derivatives are more active and less toxic than cyclosporine A.

Deoxycholic acid derivatives were designed as P-glycoprotein (Pgp, ABCB1) inhibitors. Thus the synthesis and the biological activity of methyl deoxycholate derivatives 5-10 and their ether analogs 15-20 have been reported. The potency of these compounds to modulate Pgp-mediated MDR was evaluated through daunorubicin accumulation and potentiation of doxorubicin cytotoxicity in K562/R7 multidrug resistant cells overexpressing Pgp. In parallel, their intrinsic toxicity was appreciated on K562 sensitive cells. Methyl 12α-[(2R or 2S) tetrahydro-2H-pyran-2-yloxy]-3-oxo-5β-cholan-24-oate 9b has shown a good efficiency as a Pgp inhibitor and a low intrinsic toxicity. Therefore, this derivative constitutes a new lead compound which can be used as a starting point to improve the design of non-toxic Pgp modulators.