Tetrahydropyrazolo[1,5-a]pyridine-fused steroids and their in vitro biological evaluation in prostate cancer

0507951 - ÚEB 2020 RIV FR eng J - Journal Article
Jorda, Radek - Lopes, S. M.M. - Řezníčková, Eva - Ajani, H. - Pereira, A. V. - Gomes, C. S.B. - Pinho e Melo, T. M.V.D.
Tetrahydropyrazolo[1,5-a]pyridine-fused steroids and their in vitro biological evaluation in prostate cancer.
European Journal of Medicinal Chemistry. Roč. 178, SEP 15 (2019), s. 168-176. ISSN 0223-5234. E-ISSN 1768-3254
Institutional support: RVO:61389030
Keywords : Androgen * Galeterone * Prostate * pyrazolo[1,5-a]pyridine * Steroid
OECD category: Oncology
Impact factor: 5.573, year: 2019
Method of publishing: Open access
http://dx.doi.org/10.1016/j.ejmech.2019.05.064

The androgen receptor (AR) is a steroid hormone receptor and its high expression and disruption of its regulation are strongly implicated in prostate cancer (PCa) development. One of the current therapies includes application of steroidal antiandrogens leading to blockade of the AR action by the abrogation of AR-mediated signaling. We introduced here novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused steroidal compounds, described their synthesis based on [8π+2π] cycloaddition reactions of diazafulvenium methides with different steroidal scaffolds and showed their biological evaluation in different prostate cancer cell lines in vitro. Our results showed the ability of novel compounds to suppress the expression of known androgen receptor targets, Nkx3.1 and PSA in two prostate cell lines, 22Rv1 and VCaP. Candidate compound diminished the transcription of AR-regulated genes in the reporter cell line in a concentration-dependent manner. Antiproliferative activity of the most promising steroid was studied by clonogenic assay and induction of apoptosis in treated cells was documented by immunoblot detection of cleaved PARP.
Permanent Link: http://hdl.handle.net/11104/0298976