Tetrahydropyrazolo[1,5-a]pyridine-fused steroids and their in vitro biological evaluation in prostate cancer
Language English Country France Media print-electronic
Document type Journal Article
PubMed
31181481
DOI
10.1016/j.ejmech.2019.05.064
PII: S0223-5234(19)30478-7
Knihovny.cz E-resources
- Keywords
- Androgen, Galeterone, Prostate, Steroid, pyrazolo[1,5-a]pyridine,
- MeSH
- Receptors, Androgen metabolism MeSH
- Homeodomain Proteins metabolism MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Prostatic Neoplasms drug therapy MeSH
- Antineoplastic Agents chemical synthesis metabolism pharmacology MeSH
- Pyrazoles chemical synthesis metabolism pharmacology MeSH
- Pyridines chemical synthesis metabolism pharmacology MeSH
- Molecular Docking Simulation MeSH
- Steroids chemical synthesis metabolism pharmacology MeSH
- Transcription Factors metabolism MeSH
- Binding Sites MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Receptors, Androgen MeSH
- AR protein, human MeSH Browser
- Homeodomain Proteins MeSH
- NKX3-1 protein, human MeSH Browser
- Antineoplastic Agents MeSH
- Pyrazoles MeSH
- Pyridines MeSH
- Steroids MeSH
- Transcription Factors MeSH
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.
CQC and Department of Chemistry University of Coimbra 3004 535 Coimbra Portugal
Structural Genomics Consortium University of Toronto Toronto ON M5G 1L7 Canada
References provided by Crossref.org
Synthesis and Biological Evaluation of New Isoxazolyl Steroids as Anti-Prostate Cancer Agents
