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Steroids. 2016 Dec;116:5-12. doi: 10.1016/j.steroids.2016.09.017. Epub 2016 Sep 30.

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

Author information

1
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.
2
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.
3
Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, 8 avenue Rockefeller, F-69373 Lyon Cedex 08, France.
4
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.

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.

KEYWORDS:

Deoxycholic acid derivatives; Multidrug resistance; P-glycoprotein inhibitors

PMID:
27697501
DOI:
10.1016/j.steroids.2016.09.017
[Indexed for MEDLINE]

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