Second-generation testosterone-platinum(II) hybrids for site-specific treatment of androgen receptor positive prostate cancer: Design, synthesis and antiproliferative activity

• Published in: European journal of medicinal chemistry 2019-10, Vol.179, p.660-666
• Main Authors: Ouellette, Vincent, Côté, Marie-France, Gaudreault, René C., Tajmir-Riahi, Heidar-Ali, Bérubé, Gervais
• Format: Article
• Language: English
• Subjects: Drug-targeting; Hybrid anticancer agent; Prostate cancer; SRB assay; Testosterone
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.06.090

Prostate cancer is the most diagnosed type of cancer in men in Canada. One out of eight men will be stricken with this disease during the course of his life. It is noteworthy that, at initial diagnoses 80–90% of cancers are androgen dependent. Hence, the androgen receptor is a viable biological target to be considered for drug targeting. We have developed a new generation of testosterone-Pt(II) hybrids for site-specific treatment of hormone-dependent prostate cancer. The hybrid molecules are made from testosterone using an eight-step reaction sequence with about 7% overall yield. They are linked with a stronger tether chain between the testosterone moiety and the Pt(II) moiety in comparison to our first generation hybrids. The new hybrids were tested on hormone-dependent and –independent prostate cancer cell lines. The hybrid 3a presents the best antiproliferative activity and was selective on hormone-dependent prostate cancer with IC50 of 2.2 μM on LNCaP (AR+) in comparison to 13.3 μM on PC3 (AR-) and 8.8 μM on DU145 (AR-) prostate cancer cells. On the same cell lines, CDDP displayed IC50 of 2.1 μM, 0.5 μM and 1.0 μM, respectively. Remarkably, hybrid 3a was inactive on both colon carcinoma (HT-29) and normal human adult keratinocyte cells (HaCat) with an IC50 of >25 μM. This is not the case for CDDP showing IC50 of 1.3 μM and 5.1 μM on HT-29 and HaCat cells, respectively. The potential for selective activity on androgen-receptor positive prostate cancer cells is confirmed with hybrid 3a giving new hope for an efficient and less toxic platinum-based treatment of prostate cancer patients. [Display omitted] •Novel testosterone-platinum(II) hybrids are reported.•The best hybrid exhibits IC50 in of 2.2 μM on AR + prostate cancer cells (LNCaP).•The best hybrid was selective on AR + LNCaP cells and was as active as cisplatin.•The best hybrid was inactive on normal human adult keratinocyte cells (HaCaT).•The precursor ligands showed significant antiproliferative activity.