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.
- MeSH
- androgenní receptory metabolismus MeSH
- antitumorózní látky chemická syntéza metabolismus farmakologie MeSH
- homeodoménové proteiny metabolismus MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory prostaty farmakoterapie MeSH
- pyrazoly chemická syntéza metabolismus farmakologie MeSH
- pyridiny chemická syntéza metabolismus farmakologie MeSH
- simulace molekulového dockingu MeSH
- steroidy chemická syntéza metabolismus farmakologie MeSH
- transkripční faktory metabolismus MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Functionalized dipyrromethanes were synthesized by hetero-Diels-Alder reactions of nitroso- and azoalkenes and screened for their in vitro activity as anticancer agents. The studied dipyrromethanes were tested against leukemia and lymphoma cell lines, and showed GI50 values in the mid-micromolar range. The pro-apoptotic activities of two candidates, (E)-1-(2'-ethoxycarbonylhydrazono-1'-benzyl-1H-tetrazol-5-yl)-5,5'-diethyldipyrromethane and (E)-1-(2'-p-nitrophenyl-2'-hydroxyiminoethyl)-5-phenyldipyrromethane, and their effects on the cell cycle are described. The latter compound was found to decrease the S-phase cell population in a dose-dependent manner and to irreversibly block cells in the G2 /M phase.
- MeSH
- apoptóza účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- pyrroly farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
