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: Marc Rolland de Ravel, Ghina Alameh, Maxime Melikian, Zahia Mahiout, Agnès Emptoz-Bonneton, Eva-Laure Matera, Thierry Lomberget, Roland Barret, Luc Rocheblave, Nadia Walchshofer, Sonia Beltran, Lucienne El Jawad, Elisabeth Mappus, Catherine Grenot, Michel Pugeat, Charles Dumontet, Marc Le Borgne, Claude Yves Cuilleron
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 4 Pg. 1832-45 (Feb 26 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 25634041 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Progesterone

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• Cell Survival (drug effects)
• Crystallography, X-Ray
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• K562 Cells
• Leukemia, Erythroblastic, Acute (drug therapy, metabolism, pathology)
• Models, Molecular
• Molecular Conformation
• Progesterone (chemical synthesis, chemistry, pharmacology)
• Tumor Cells, Cultured