Journal of Medicinal Chemistry p. 1832 - 1845 (2015)
Update date:2022-08-15
Topics:
De Ravel, Marc Rolland
Alameh, Ghina
Melikian, Maxime
Mahiout, Zahia
Emptoz-Bonneton, Agnès
Matera, Eva-Laure
Lomberget, Thierry
Barret, Roland
Rocheblave, Luc
Walchshofer, Nadia
Beltran, Sonia
El Jawad, Lucienne
Mappus, Elisabeth
Grenot, Catherine
Pugeat, Michel
Dumontet, Charles
Le Borgne, Marc
Cuilleron, Claude Yves
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.
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