Rocheblave Luc, de Ravel Marc Rolland, Monniot Elodie, Tavenard Jeremy, Cuilleron Claude-Yves, Grenot Catherine, Radix Sylvie, Matera Eva-Laure, Dumontet Charles, Walchshofer Nadia
Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, 8 avenue Rockefeller, F-69373 Lyon Cedex 08, France.
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.
Steroids. 2016 Dec;116:5-12. doi: 10.1016/j.steroids.2016.09.017. Epub 2016 Sep 30.
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.
脱氧胆酸衍生物被设计为P-糖蛋白（Pgp，ABCB1）抑制剂。因此，已报道了脱氧胆酸甲酯衍生物5-10及其醚类似物15-20的合成及生物活性。通过柔红霉素积累以及阿霉素对过表达Pgp的K562/R7多药耐药细胞的细胞毒性增强，评估了这些化合物调节Pgp介导的多药耐药性的能力。同时，在K562敏感细胞上评估了它们的内在毒性。甲基12α-[(2R或2S)四氢-2H-吡喃-2-基氧基]-3-氧代-5β-胆烷-24-酸酯9b已显示出作为Pgp抑制剂的良好效果以及较低的内在毒性。因此，该衍生物构成了一种新的先导化合物，可作为改进无毒Pgp调节剂设计的起点。
