First synthesis of separable isomeric testosterone dimers showing differential activities on prostate cancer cells

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 7; pp. 2078 - 2081
• Main Authors: Bastien, Dominic, Leblanc, Valérie, Asselin, Éric, Bérubé, Gervais
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.04.2010; Elsevier
• Subjects: Androgen Antagonists - chemical synthesis; Androgen Antagonists - chemistry; Androgen Antagonists - pharmacology; Androgen receptor; Antineoplastic agents; Antineoplastic Agents, Hormonal - chemical synthesis; Antineoplastic Agents, Hormonal - chemistry; Antineoplastic Agents, Hormonal - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Crystallography, X-Ray; Dimers; Drug Screening Assays, Antitumor; General aspects; Humans; Isomerism; Male; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Prostate cancer; Prostatic Neoplasms - drug therapy; Testosterone; Testosterone - analogs & derivatives; Testosterone - chemical synthesis; Testosterone - chemistry; Testosterone - pharmacology; Testosterone; Dimers; Prostate cancer; Androgen receptor; Antineoplastic agent; Human; Stereoisomer; Cytotoxicity; In vitro; Biological activity; Cell line; Dimer; Chemical synthesis; Prostate; Tumor cell; Butene derivatives
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.02.077

The synthesis of two testosterone dimers is reported. The synthesis led to two separable isomeric dimers ( trans and cis, 2:1). X-ray diffraction crystallography confirmed the structure of the minor isomer. MTT assays showed that the cis dimer has the best activity against human prostate cancer cell lines. The synthesis of two separable isomeric testosterone dimers is reported. The dimers are made from testosterone in a 5 step sequence and with 36% overall yield. The key dimerization step was performed using Hoveyda–Grubb’s metathesis catalysts on 7α-allyltestosterone with 75% yield. The synthesis led to separable isomeric dimers ( trans and cis, 2:1). X-ray diffraction crystallography, performed on monocrystal of the minor isomer, confirms the cis geometry of the double bound between the two testosterone units. MTT assays showed that the cis dimer has the highest activity against prostate cancer cell lines. The novel cis dimer is more active than the antiandrogen cyproterone acetate indicating the possible therapeutic value of this molecule.