Synthesis of hydrocortisone esters targeting androgen and glucocorticoid receptors in prostate cancer in vitro
Jazyk angličtina Země Velká Británie, Anglie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
36773737
DOI
10.1016/j.jsbmb.2023.106269
PII: S0960-0760(23)00024-9
Knihovny.cz E-zdroje
- Klíčová slova
- Androgen receptor, Castration resistant prostate cancer, Glucocorticoid receptor, Hydrocortisone derivatives, Prostate cancer, Transcriptional activity,
- MeSH
- androgenní receptory * genetika chemie MeSH
- androgeny farmakologie MeSH
- antagonisté androgenů farmakologie MeSH
- chemorezistence MeSH
- hydrokortison farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory prostaty rezistentní na kastraci * farmakoterapie metabolismus MeSH
- nitrily farmakologie MeSH
- receptory glukokortikoidů MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- androgenní receptory * MeSH
- androgeny MeSH
- antagonisté androgenů MeSH
- enzalutamide MeSH Prohlížeč
- hydrokortison MeSH
- nitrily MeSH
- receptory glukokortikoidů MeSH
Androgen and glucocorticoid receptors have been recently described as key players in processes related to prostate cancer and mainly androgen receptor's inactivation was shown as an effective way for the prostate cancer treatment. Unfortunately, androgen deprivation therapy usually loses its effectivity and the disease frequently progresses into castration-resistant prostate cancer with poor prognosis. The role of the glucocorticoid receptor is associated with the mechanism of resistance; therefore, pharmacological targeting of glucocorticoid receptor in combination with antiandrogen treatment was shown as an alternative approach in the prostate cancer treatment. We introduce here the synthesis of novel 17α- and/or 21-ester or carbamate derivatives of hydrocortisone and evaluation of their biological activity towards androgen and glucocorticoid receptors in different prostate cancer cell lines. A 17α-butyryloxy-21-(alkyl)carbamoyloxy derivative 14 was found to diminish the transcriptional activity of both receptors (in single-digit micromolar range), with comparable potency to enzalutamide towards the androgen receptor, but weaker potency compared to mifepristone towards the glucocorticoid receptor. Lead compound inhibited proliferation and the formation of cell colonies in both androgen and glucocortiocid receptors-positive prostate cancer cell lines in low micromolar concentrations. Candidate compound 14 showed to interact with both receptors in cells and inhibited the translocation of receptors to nucleus and their activation phoshorylation. Moreover, binding to receptor's ligand binding domains was assessed by molecular modelling. Lead compound also induced the accumulation of cells in G1 phase and its combination with enzalutamide was shown to be more effective than enzalutamide alone.
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