Šestić Tijana Lj, Bekić Sofija S, Marinović Maja A, Kvasnicová Marie, Štenclová Tereza, Rárová Lucie, Ćelić Andjelka S, Petri Edward T, Ajduković Jovana J, Strnad Miroslav, Savić Marina P
Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, Novi Sad, Serbia.
Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 2, Novi Sad, Serbia.
Eur J Med Chem. 2025 Oct 15;296:117850. doi: 10.1016/j.ejmech.2025.117850. Epub 2025 Jun 6.
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 IC 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.
将杂环插入甾体核心可以增强生物活性，提高选择性，并减少癌症治疗潜在药物中的副作用。本研究描述了结合内酯、内酰胺或吡啶部分的新型噻唑啉、噻二唑啉和噻唑烷酮甾体化合物的合成。这些甾体杂化分子可能是药物设计的潜在候选物，具有改善的生物活性和生物利用度。起始原料雄烯二酮或脱氢表雄酮通过多相合成修饰为硫代腙雄甾烷衍生物，这是合成新型杂环化合物的直接前体。测试了它们对五种癌细胞系的细胞毒性：乳腺腺癌细胞（MCF7）、急性淋巴细胞白血病（CCRF-CEM）、宫颈癌细胞（HeLa）、激素非依赖性（DU 145）和激素敏感性前列腺癌细胞（LNCaP），以及对正常皮肤成纤维细胞（BJ）的细胞毒性。发现化合物5和16具有最高的选择性，两者均能诱导HeLa细胞凋亡。还使用酵母细胞中的荧光测定法评估了新化合物对雌激素受体α（ERα）、雌激素受体β（ERβ）、雄激素受体（AR）或糖皮质激素受体（GR）的配体结合域（LBD）的相对结合亲和力，其中噻唑衍生物13对ERα表现出最高的结合亲和力，而噻唑烷酮7对ERβ表现出强烈的选择性亲和力。此外，通过荧光光谱法评估了对人醛糖酮还原酶1C3和1C4（AKR1C3和AKR1C4）的抑制潜力，乙酰氨基噻二唑啉21对AKR1C3的IC值略高于参考抑制剂布洛芬。基于体外实验，使用分子对接研究为对特定蛋白质表现出最强亲和力的化合物提出蛋白质-配体结合模型。总之，我们的结果表明，测试的杂环衍生物对激素依赖性癌细胞具有活性，是开发新型治疗药物的有希望的先导化合物。
