New steroidal 17β-carboxy derivatives present anti-5α-reductase activity and anti-proliferative effects in a human androgen-responsive prostate cancer cell line

• Published in: Biochimie 2013-11, Vol.95 (11), p.2097-2106
• Main Authors: Amaral, Cristina, Varela, Carla, Correia-da-Silva, Georgina, Tavares da Silva, Elisiário, Carvalho, Rui A., Costa, Saul C.P., Cunha, Sara C., Fernandes, José O., Teixeira, Natércia, Roleira, Fernanda M.F.
• Format: Article
• Language: English
• Subjects: Benign prostate hyperplasia; Cell Line, Tumor; Cell Proliferation - drug effects; Cholestenone 5 alpha-Reductase - antagonists & inhibitors; Cholestenone 5 alpha-Reductase - metabolism; Dihydrotestosterone - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Finasteride; Humans; LNCaP cells; Male; Prostate - metabolism; Prostate - pathology; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Steroidal 5α-reductase inhibitors; Testosterone - metabolism
• ISSN: 0300-9084; 1638-6183
• DOI: 10.1016/j.biochi.2013.07.023

The androgens testosterone (T) and dihydrotestosterone (DHT), besides playing an important role in prostate development and growth, are also responsible for the development and progression of benign prostate hyperplasia (BPH) and prostate cancer. Therefore, the actions of these hormones can be antagonized by preventing the irreversible conversion of T into DHT by inhibiting 5α-reductase (5α-R). This has been a useful therapeutic approach for the referred diseases and can be achieved by using 5α-reductase inhibitors (RIs). Steroidal RIs, finasteride and dutasteride, are used in clinic for BPH treatment and were also proposed for chemoprevention of prostate cancer. Nevertheless, due to the increase in bone and muscle loss, impotency and occurrence of high-grade prostate tumours, it is important to seek for other potent and specific molecules with lower side effects. In the present work, we designed and synthesized steroids with the 3-keto-Δ4 moiety in the A-ring, as in the 5α-R substrate T, and with carboxamide, carboxyester or carboxylic acid functions at the C-17β position. The inhibitory 5α-R activity, in human prostate microsomes, as well as the anti-proliferative effects of the most potent compounds, in a human androgen-responsive prostate cancer cell line (LNCaP cells), were investigated. Our results showed that steroids 3, 4 and 5 are good RIs, which suggest that C-17β lipophylic amides favour 5α-R inhibition. Moreover, these steroids induce a decrease in cell viability of stimulated LNCaP cells, in a 5α-R dependent-manner, similarly to finasteride. [Display omitted] •Design and synthesis of new steroids as potential 5α-reductase (5α-R) inhibitors (RIs).•Evaluation of the anti-5α-reductase activity and anti-proliferative effects of steroids.•Steroids with 3-keto-Δ4 moiety in the A-ring and C-17β lipophilic amides are good RIs.•The RIs decrease LNCaP cells viability in a 5α-R dependent-manner similarly to finasteride.