Abstract：
The distinct chemical structure of thiourea derivatives provides them with an advantage in selectively targeting cancer cells. In our previous study, we selected the most potent compounds, 2 and 8, with 3,4-dichloro- and 3-trifluoromethylphenyl substituents, respectively, across colorectal (SW480 and SW620), prostate (PC3), and leukemia (K-562) cancer cell lines, as well as non-tumor HaCaT cells. Our research has demonstrated their anticancer potential by targeting key molecular pathways involved in cancer progression, including caspase 3/7 activation, NF-κB (Nuclear Factor Kappa-light-chain-enhancer of activated B cells) activation decrease, VEGF (Vascular Endothelial Growth Factor) secretion, ROS (Reactive Oxygen Species) production, and metabolite profile alterations. Notably, these processes exhibited no significant alterations in HaCaT cells. The effectiveness of the studied compounds was also tested on spheroids (3D culture). Both derivatives 2 and 8 increased caspase activity, decreased ROS production and NF-κB activation, and suppressed the release of VEGF in cancer cells. Metabolomic analysis revealed intriguing shifts in cancer cell metabolic profiles, particularly in lipids and pyrimidines metabolism. Assessment of cell viability in 3D spheroids showed that SW620 cells exhibited better sensitivity to compound 2 than 8. In summary, structural modifications of the thiourea terminal components, particularly dihalogenophenyl derivative 2 and para-substituted analog 8, demonstrate their potential as anticancer agents while preserving safety for normal cells.
摘要：
硫脲衍生物的独特化学结构为它们提供了选择性靶向癌细胞的优势。在我们之前的研究中,我们选择了最有效的化合物，2和8，具有3,4-二氯-和3-三氟甲基苯基取代基，分别,跨结肠直肠（SW480和SW620），前列腺（PC3），和白血病（K-562）癌细胞系，以及非肿瘤HaCaT细胞。我们的研究通过靶向参与癌症进展的关键分子途径证明了它们的抗癌潜力，包括胱天蛋白酶3/7激活，NF-κB（活化B细胞的核因子κ轻链增强子）活化降低，VEGF（血管内皮生长因子）分泌，ROS（活性氧）生产，和代谢物谱改变。值得注意的是,这些过程在HaCaT细胞中没有表现出显著的改变。还在球状体(3D培养)上测试了所研究化合物的有效性。衍生物2和8都增加了半胱天冬酶活性，减少ROS产生和NF-κB激活，抑制癌细胞中VEGF的释放。代谢组学分析揭示了癌细胞代谢谱的有趣变化，特别是在脂质和嘧啶代谢中。3D球状体中细胞活力的评估显示,SW620细胞对化合物2表现出比8更好的敏感性。总之,硫脲末端组分的结构修饰，特别是二卤代苯基衍生物2和对位取代的类似物8证明了它们作为抗癌剂的潜力,同时保持正常细胞的安全性。
