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

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Cristina Amaral (Author) Other; Carla Varela (Author) Other; Georgina Correia da Silva (Author) FFUP; Elisiario Tavares da Silva (Author) Other; Rui A Carvalho (Author) Other; Saul C P Costa (Author) Other; Sara C Cunha (Author) Other; Jose O Fernandes (Author) FFUP; Natercia Teixeira (Author) FFUP; Fernanda M F Roleira (Author) Other

Journal

Title: Biochimie

Vol. 95

Pages: 2097-2106

ISSN: 0300-9084

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 9 Citations

Scopus - 10 Citations

Scientific classification

FOS: Natural sciences > Biological sciences

Other information

Authenticus ID: P-006-6BJ

DOI: 10.1016/j.biochi.2013.07.023

Abstract (EN): 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 5 alpha-reductase (5 alpha-R). This has been a useful therapeutic approach for the referred diseases and can be achieved by using 5 alpha-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-Delta(4) moiety in the A-ring, as in the 5 alpha-R substrate T, and with carboxamide, carboxyester or carboxylic acid functions at the C-17 beta position. The inhibitory 5 alpha-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-17 beta lipophylic amides favour 5 alpha-R inhibition. Moreover, these steroids induce a decrease in cell viability of stimulated LNCaP cells, in a 5 alpha-R dependent-manner, similarly to finasteride.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10