title: Synthesis of new steroidal inhibitors of P-glycoprotein-mediated multidrug resistance and biological evaluation on K562/R7 erythroleukemia cells.
abstract: A simple route for improving the potency of progesterone as a modulator of P-gp-mediated multidrug resistance was established by esterification or etherification of hydroxylated 5α/β-pregnane-3,20-dione or 5β-cholan-3-one precursors. X-ray crystallography of representative 7α-, 11α-, and 17α-(2'R/S)-O-tetrahydropyranyl ether diastereoisomers revealed different combinations of axial-equatorial configurations of the anomeric oxygen. Substantial stimulation of accumulation and chemosensitization was observed on K562/R7 erythroleukemia cells resistant to doxorubicin, especially using 7α,11α-O-disubstituted derivatives of 5α/β-pregnane-3,20-dione, among which the 5β-H-7α-benzoyloxy-11α-(2'R)-O-tetrahydropyranyl ether 22a revealed promising properties (accumulation index 2.9, IC50 0.5 μM versus 1.2 and 10.6 μM for progesterone), slightly overcoming those of verapamil and cyclosporin A. Several 7α,12α-O-disubstituted derivatives of 5β-cholan-3-one proved even more active, especially the 7α-O-methoxymethyl-12α-benzoate 56 (accumulation index 3.8, IC50 0.2 μM). The panel of modulating effects from different O-substitutions at a same position suggests a structural influence of the substituent completing a simple protection against stimulating effects of hydroxyl groups on P-gp-mediated transport.
authors: Centre de Recherche en Cancérologie de Lyon - Université Claude Bernard Lyon 1 , INSERM U1052-CNRS UMR5286, Centre Léon Bérard-Cheney D, 28 rue Laënnec, Lyon 69373 Cedex 08, France.
authors: Marc Rolland
authors: MR
authors: de Ravel
authors: Ghina
authors: G
authors: Alameh
authors: Maxime
authors: M
authors: Melikian
authors: Zahia
authors: Z
authors: Mahiout
authors: Agnès
authors: A
authors: Emptoz-Bonneton
authors: Eva-Laure
authors: EL
authors: Matera
authors: Thierry
authors: T
authors: Lomberget
authors: Roland
authors: R
authors: Barret
authors: Luc
authors: L
authors: Rocheblave
authors: Nadia
authors: N
authors: Walchshofer
authors: Sonia
authors: S
authors: Beltran
authors: Lucienne
authors: L
authors: El Jawad
authors: Elisabeth
authors: E
authors: Mappus
authors: Catherine
authors: C
authors: Grenot
authors: Michel
authors: M
authors: Pugeat
authors: Charles
authors: C
authors: Dumontet
authors: Marc
authors: M
authors: Le Borgne
authors: Claude Yves
authors: CY
authors: Cuilleron
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008958:Models, Molecular; D008968:Molecular Conformation; D011374:Progesterone / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011374:Progesterone