title: Deoxycholic acid derivatives as inhibitors of P-glycoprotein-mediated multidrug efflux.
abstract: 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.
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, 8 avenue Rockefeller, F-69373 Lyon Cedex 08, France. Electronic address: luc.rocheblave@univ-lyon1.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Rocheblave
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS UMR5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Cheney D, 28 rue Laënnec, F-69373 Lyon Cedex 08, France.
authors.forename: Marc Rolland
authors.initials: MR
authors.lastname: de Ravel
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, 8 avenue Rockefeller, F-69373 Lyon Cedex 08, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Monniot
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, 8 avenue Rockefeller, F-69373 Lyon Cedex 08, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Tavenard
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, 8 avenue Rockefeller, F-69373 Lyon Cedex 08, France.
authors.forename: Claude-Yves
authors.initials: CY
authors.lastname: Cuilleron
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, 8 avenue Rockefeller, F-69373 Lyon Cedex 08, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Grenot
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, 8 avenue Rockefeller, F-69373 Lyon Cedex 08, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Radix
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS UMR5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Cheney D, 28 rue Laënnec, F-69373 Lyon Cedex 08, France.
authors.forename: Eva-Laure
authors.initials: EL
authors.lastname: Matera
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS UMR5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Cheney D, 28 rue Laënnec, F-69373 Lyon Cedex 08, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, 8 avenue Rockefeller, F-69373 Lyon Cedex 08, France. Electronic address: nadia.walchshofer@univ-lyon1.fr.
authors.forename: Nadia
authors.initials: N
authors.lastname: Walchshofer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003630:Daunorubicin / Q000378:metabolism*; D003840:Deoxycholic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004317:Doxorubicin / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020014:K562 Cells
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003840:Deoxycholic Acid; D004317:Doxorubicin; D003630:Daunorubicin
keywords: Deoxycholic acid derivatives; Multidrug resistance; P-glycoprotein inhibitors