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 α (ERα), estrogen receptor β (ERβ), androgen receptor (AR) or glucocorticoid receptor (GR) using a fluorescent assay in yeast cells, where thiazole derivative 13 exhibited the highest binding affinity for ERα, while thiazolidinone 7 showed strong selective affinity for ERβ. 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.

Department of Biology and Ecology Faculty of Sciences University of Novi Sad Trg Dositeja Obradovića 2 Novi Sad Serbia

Department of Chemistry Biochemistry and Environmental Protection Faculty of Sciences University of Novi Sad Trg Dositeja Obradovića 3 Novi Sad Serbia

Department of Experimental Biology Palacký University Slechtitelu 27 779 00 Olomouc Czech Republic

Department of Experimental Biology Palacký University Slechtitelu 27 779 00 Olomouc Czech Republic; Laboratory of Growth Regulators Faculty of Science Palacký University and Institute of Experimental Botany of the Czech Academy of Sciences Slechtitelu 27 Olomouc 779 00 Czech Republic

Laboratory of Growth Regulators Faculty of Science Palacký University and Institute of Experimental Botany of the Czech Academy of Sciences Slechtitelu 27 Olomouc 779 00 Czech Republic

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