Prostate cancer is a major public health problem worldwide. In the United-States, prostate cancer is ranked first of all new cancer cases diagnosed in men and it is the second most lethal cancer. Antiandrogens are normally used in clinic to slow down the progression of androgen-sensitive (AR+) prostate cancer inducing prolonged remission without definite cure. In general, 10 years after the initial treatment of early prostate cancers, 19% of patients will experience local tumor progression, 15% distant metastases and 10% will die. Furthermore, advanced prostate cancers quickly (18 to 24 months) become androgen-insensitive (AR-) and antihormone therapy becomes ineffective. At this point, the median survival of approved drug combination treatments is then under 20 months. Consequently, the search for new, more selective and efficient treatments is still a subject of intense research.

To that end, we used the natural tropism of testosterone for prostate tissues to target platinum(II) complexes to prostate cancer cells. The platinum complexes were linked to the 7α position on testosterone as it is located between the 3-carbonyl and 17-hydroxyl groups involved in key hydrogen bonds essential for androgen receptor interactions. L- and D-2-pyridylalanine, L-histidine and L-4-thiazolylalanine derivatives were linked to 17β-acetyl-testosterone selected to chelate platinum(II). Four new amino acid platinum(II) complexes were prepared (compounds 1a-1d), characterized and evaluated for their antiproliferative activity on LNCaP (AR+), PC3 (AR-) and DU145 (AR-) human prostate adenocarcinoma cancer cell lines.

The new testosterone-platinum(II) complexes exhibited antiproliferative activities at the micromolar level on all prostate cancer cell lines tested. Structure-activity relationships show that the stereochemistry of amino acids (compounds 1a, b) does not affect the antiproliferative activity. Moreover, the replacement of a pyridinyl moiety by an imidazolyl group (compound 1c) decreased the activity by up to 10 fold whereas the replacement by a thiazolyl group (compound 1d) showed an antiproliferative activity between 2.5 to 8.0 times higher than that of cisplatin.

The innovative design and the significant activity of our testosterone-platinum(II) complexes toward AR+ and AR- prostate cancer cells suggest that they might be useful for treatment of advanced prostate cancers.

Citation Format: Sébastien Fortin, Kevin Brasseur, Nathalie Morin, Éric Asselin, Gervais Bérubé. Synthesis and antiproliferative activity of novel 17β-acetyl-testosterone-7α-platinum(II) hybrids designed for the treatment of human prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2474. doi:10.1158/1538-7445.AM2013-2474