title: Chemical synthesis and biological activities of 16alpha-derivatives of 5alpha-androstane-3alpha,17beta-diol as antiandrogens.
abstract: In our efforts to develop compounds with therapeutic potential as antiandrogens, we synthesized a series of 5alpha-androstane-3alpha,17beta-diol derivatives with a fixed side-chain length of 3-methylenes at C-16alpha, but bearing a diversity of functional groups at the end. Among these, the chloride induced the best antiproliferative activity on androgen-sensitive Shionogi cells. Substituting the OH at C-3 by a methoxy group showed the importance of the OH. Moreover, its transformation into a ketone increased the androgen receptor (AR) binding but decreased the antiproliferative activity and induced a proliferative effect on Shionogi cells. These results confirm the importance of keeping a 5alpha-androstane-3alpha,17beta-diol nucleus instead of a dihydrotestosterone nucleus. Variable side-chain lengths of 2-, 3-, 4-, and 6-methylenes at C-16alpha were investigated and the optimal length was found to be 3-methylenes. Although exhibiting a weak AR binding affinity, 16alpha-(3'-chloropropyl)-5alpha-androstane-3alpha,17beta-diol (15) provided an antiproliferative activity on Shionogi cells similar to that of pure non-steroidal antiandrogen hydroxy-flutamide (77% and 67%, respectively, at 0.1 microM). The new steroidal compound, 15, thus constitutes a good starting point for development of future antiandrogens with a therapeutic potential against prostate cancer.
authors.affiliation: Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, Centre Hospitalier Universitaire de Québec (CHUQ), Pavillon CHUL and Université Laval, Que., Canada G1V 4G2.
authors.forename: Jenny
authors.initials: J
authors.lastname: Roy
authors.forename: Rock
authors.initials: R
authors.lastname: Breton
authors.forename: Céline
authors.initials: C
authors.lastname: Martel
authors.forename: Fernand
authors.initials: F
authors.lastname: Labrie
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D015113:Androstane-3,17-diol / Q000138:chemical synthesis* / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011944:Receptors, Androgen / Q000187:drug effects; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D007202:Indicators and Reagents; D011944:Receptors, Androgen; D015113:Androstane-3,17-diol