ABSTRACT
Synthesis of 21,22-cyclosteroids has been achieved starting from pregnenolone acetate. The key transformation was the Kulinkovich reaction of 17-vinyl steroids with esters. The resulting cyclopropanols were further subjected to three-membered ring-opening under various conditions including to base-, palladium or visible light-promoted isomerization and cross-coupling reaction. A number of steroidal Δ2-6-ketones and 3ß-hydroxy-Δ5-enes with functional groups at C-21 - C-23 have been synthesized via the 21,22-cyclosteroids. The antiproliferative and antihormonal activity of the obtained compounds on the cell lines of prostate (22Rv1) and breast (MCF-7) cancer was studied. The androgen receptor activity was assessed by reporter assay when the expression of signalling proteins was evaluated by immunoblotting. (20S,22R)-22-Acetoxy-21,22-cyclo-5α-cholest-5-ene with the moderate antiandrogenic potency revealed IC50 values of 18.4 ± 1.2 and 14.6 ± 1.4 µM against MCF-7 and 22Rv1 cells, respectively, and its effects on the expression of AR-V7, cyclin D1 and BCL2 were explored.
Subject(s)
Antineoplastic Agents , Cyclosteroids , Humans , Male , Cell Line, Tumor , Cell Proliferation , Cyclosteroids/chemistry , Cyclosteroids/pharmacology , Imidazoles , Pregnenolone , Receptors, Androgen/metabolism , Steroids , Breast Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacologySubject(s)
Androgen Antagonists , Homosteroids/pharmacology , Testosterone Congeners , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/metabolism , Animals , Cyclosteroids/pharmacology , Cytosol/metabolism , Dihydrotestosterone/metabolism , In Vitro Techniques , Male , Prostate/metabolism , Rats , Receptors, Androgen/metabolism , Seminal Vesicles/drug effects , Sex Hormone-Binding Globulin/metabolism , Steroids/metabolism , Structure-Activity RelationshipABSTRACT
Two different synthetic routes have been used to synthesize a series of cyclopropyl conjugated ketones in which 4alpha,6-unsaturation replaces the usual 4,5-unsaturation. The synthetic routes involve intramolecular ketocarbene addition to a 5-6 double bond and intramolecular 1,3-elimination of 6beta-substituted 5beta-3-keto steroids. Both routes give 5beta products. The analogs of progesterone, testoterone acetate, and norethisterone have been prepared and shown to be remarkably biologically inactive when compared with the corresponding standard. Possible reasons for such inactivity are discussed.
