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

• Published in: Steroids 2016-12, Vol.116, p.5-12
• Main Authors: Rocheblave, Luc, de Ravel, Marc Rolland, Monniot, Elodie, Tavenard, Jeremy, Cuilleron, Claude-Yves, Grenot, Catherine, Radix, Sylvie, Matera, Eva-Laure, Dumontet, Charles, Walchshofer, Nadia
• Format: Article
• Language: English
• Subjects: ATP Binding Cassette Transporter, Sub-Family B - antagonists & inhibitors; ATP Binding Cassette Transporter, Sub-Family B - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Daunorubicin - metabolism; Deoxycholic Acid - analogs & derivatives; Deoxycholic Acid - chemistry; Deoxycholic Acid - pharmacology; Deoxycholic acid derivatives; Doxorubicin - metabolism; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; K562 Cells; Multidrug resistance; P-glycoprotein inhibitors
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2016.09.017

•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.