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: Jenny Roy, Rock Breton, Céline Martel, Fernand Labrie, Donald Poirier
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 15 Issue 8 Pg. 3003-18 (Apr 15 2007) ISSN: 0968-0896 [Print] England
• PMID: 17336533 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androgen Antagonists
• Antineoplastic Agents, Hormonal
• Indicators and Reagents
• Receptors, Androgen
• Androstane-3,17-diol

Topics

• Androgen Antagonists (chemical synthesis, pharmacology)
• Androstane-3,17-diol (chemical synthesis, pharmacology)
• Antineoplastic Agents, Hormonal (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Indicators and Reagents
• Magnetic Resonance Spectroscopy
• Models, Molecular
• Receptors, Androgen (drug effects)
• Spectrophotometry, Infrared
• Structure-Activity Relationship