Heterocyclic androstane derivatives targeting hormone-related cancers: Synthesis, bioactivity and docking studies

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F25%3A00638430" target="_blank" >RIV/61389030:_____/25:00638430 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/25:73631054

Výsledek na webu

<a href="https://doi.org/10.1016/j.ejmech.2025.117850" target="_blank" >https://doi.org/10.1016/j.ejmech.2025.117850</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2025.117850" target="_blank" >10.1016/j.ejmech.2025.117850</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Heterocyclic androstane derivatives targeting hormone-related cancers: Synthesis, bioactivity and docking studies

Popis výsledku v původním jazyce

Insertion of a heterocyclic ring into the steroid core could enhance bioactivity, improve selectivity and reduce side effects in potential drugs for cancer therapy. The present study describes the synthesis of new thiazoline, thiadiazoline and thiazolidinone steroid compounds combined with lactone, lactam or pyridine moieties. These steroid hybrid molecules may be potential candidates for drug design, with improved biological activity and bioavailability. The starting androstenedione or dehydroepiandrosterone were modified by multiphase synthesis into thiosemicarbazone androstane derivatives, direct precursors for the synthesis of new heterocyclic compounds. Their cytotoxicity was tested against five cancer cell lines: breast adenocarcinoma cells (MCF7), acute lymphoblastic leukemia (CCRF-CEM), cervical carcinoma cells (HeLa), hormone-independent (DU 145) and hormone-sensitive prostate cancer cells (LNCaP), as well as against normal skin fibroblasts (BJ). Compounds 5 and 16 were found to be the most selective, with both inducing apoptosis in HeLa cells. New compounds were also evaluated for their relative binding affinities for the ligand-binding domains (LBDs) of estrogen receptor alpha (ER alpha), estrogen receptor beta (ER beta), androgen receptor (AR) or glucocorticoid receptor (GR) using a fluorescent assay in yeast cells, where thiazole derivative 13 exhibited the highest binding affinity for ER alpha, while thiazolidinone 7 showed strong selective affinity for ER beta. Furthermore, inhibition potential against human aldo-keto reductase 1C3 and 1C4 (AKR1C3 and AKR1C4) was evaluated by fluorescence spectroscopy, with acetamido thiadiazoline 21 displaying an IC50 value for AKR1C3 slightly higher than the reference inhibitor ibuprofen. Molecular docking studies were used to propose protein-ligand binding models for compounds showing the strongest affinity toward specific proteins based on in vitro experiments. In summary, our results suggest that the tested heterocyclic derivatives are active against hormone-dependent cancer cells and represent promising leads for the development of novel therapeutics.

Název v anglickém jazyce

Heterocyclic androstane derivatives targeting hormone-related cancers: Synthesis, bioactivity and docking studies

Popis výsledku anglicky

Insertion of a heterocyclic ring into the steroid core could enhance bioactivity, improve selectivity and reduce side effects in potential drugs for cancer therapy. The present study describes the synthesis of new thiazoline, thiadiazoline and thiazolidinone steroid compounds combined with lactone, lactam or pyridine moieties. These steroid hybrid molecules may be potential candidates for drug design, with improved biological activity and bioavailability. The starting androstenedione or dehydroepiandrosterone were modified by multiphase synthesis into thiosemicarbazone androstane derivatives, direct precursors for the synthesis of new heterocyclic compounds. Their cytotoxicity was tested against five cancer cell lines: breast adenocarcinoma cells (MCF7), acute lymphoblastic leukemia (CCRF-CEM), cervical carcinoma cells (HeLa), hormone-independent (DU 145) and hormone-sensitive prostate cancer cells (LNCaP), as well as against normal skin fibroblasts (BJ). Compounds 5 and 16 were found to be the most selective, with both inducing apoptosis in HeLa cells. New compounds were also evaluated for their relative binding affinities for the ligand-binding domains (LBDs) of estrogen receptor alpha (ER alpha), estrogen receptor beta (ER beta), androgen receptor (AR) or glucocorticoid receptor (GR) using a fluorescent assay in yeast cells, where thiazole derivative 13 exhibited the highest binding affinity for ER alpha, while thiazolidinone 7 showed strong selective affinity for ER beta. Furthermore, inhibition potential against human aldo-keto reductase 1C3 and 1C4 (AKR1C3 and AKR1C4) was evaluated by fluorescence spectroscopy, with acetamido thiadiazoline 21 displaying an IC50 value for AKR1C3 slightly higher than the reference inhibitor ibuprofen. Molecular docking studies were used to propose protein-ligand binding models for compounds showing the strongest affinity toward specific proteins based on in vitro experiments. In summary, our results suggest that the tested heterocyclic derivatives are active against hormone-dependent cancer cells and represent promising leads for the development of novel therapeutics.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

<a href="/cs/project/GA23-05474S" target="_blank" >GA23-05474S: Modulace kináz pro cílenou léčbu hematologických a dalších malignit</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

1768-3254

Svazek periodika

296

Číslo periodika v rámci svazku

OCT 15

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

18

Strana od-do

117850

Kód UT WoS článku

001517297600001

EID výsledku v databázi Scopus

2-s2.0-105007629030