Title:New Testosterone Derivatives as Semi-Synthetic Anticancer Agents Against Prostate Cancer: Synthesis and Preliminary Biological Evaluation
Volume: 11
Issue: 6
Author(s): Nathalie Morin, Julie Bruneau, Sebastien Fortin, Kevin Brasseur, Valerie Leblanc, Eric Asselin and Gervais Berube
Affiliation:
Keywords:
Testosterone-7α-linked amides, prostate cancer, anticancer agents.
Abstract: Prostate cancer (PC) is a major health issue in the world. Treatments of localized PC are
quite efficient and usually involve surgery, radiotherapy and/or hormonal therapy. Metastatic PC is
however rarely curable to this day. Treatments of metastatic PC involve radiotherapy, chemotherapy
and hormonal treatment such as orchiectomy, antiandrogens and luteinizing hormone-releasing hormone
agonists. The suppression of tumor growth by hormonal treatment is efficient but overtime resistance
still occurs and the disease progresses. Thus, more urgently than ever there is a need for discovery
of new treatment options for castration-resistant PC (CRPC). Hence, we designed and tested a series
of amide derivatives located at position 7α of testosterone as prospective “natural” or “semisynthetic”
anticancer agents against CRPC with the goal of discovering therapeutic alternatives for the
disease. This manuscript describes an efficient path towards the target molecules that are made in only 6 or 7 chemical
steps from testosterone in good overall yields. This strategy can be used to make several compounds of interest that present
higher biological activity than the classic antiandrogen; cyproterone acetate (3). The best testosterone-7α-amide was
the N-2-pyridylethylamide (25) which was as active as the antiandrogen cyproterone acetate (3) on androgen-dependent
LNCaP cells and 2.7 times more active on androgen-independent PC3 prostate cancer cells. The results obtained show the
synthetic feasibility and the potential for future development of this unique class of semi-synthetic anticancer agents that
offer the premise of new treatment modalities for patients afflicted with CRPC.