Sorafenib, a multiple kinase inhibitor, is widely used as a first-line treatment for hepatocellular carcinoma. However, there is a need for more effective alternatives when sorafenib proves insufficient. In this study, we aimed to design a structure that surpasses sorafenib’s efficacy, leading us to synthesize sorafenib–ruthenium complexes for the first time and investigate their properties. Our results indicate that the sorafenib–ruthenium complexes exhibit superior epidermal growth factor receptor (EGFR) inhibition compared to sorafenib alone. Interestingly, among these complexes, Ru3S demonstrated high activity against various cancer cell lines including sorafenib-resistant HepG2 cells while exhibiting significantly lower cytotoxicity than sorafenib in healthy cell lines. Further evaluation of cell cycle, cell apoptosis, and antiangiogenic effects, molecular docking, and molecular dynamics studies revealed that Ru3S holds great potential as a drug candidate. Additionally, when free Ru3S was encapsulated into polymeric micelles M1, enhanced cytotoxicity on HepG2 cells was observed. Collectively, these findings position Ru3S as a promising candidate for EGFR inhibition and warrant further exploration for drug development purposes.

中文翻译：

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索拉非尼-钌配合物的合成、生物活性研究及其在抗癌药物输送系统中的应用

索拉非尼是一种多激酶抑制剂，广泛用作肝细胞癌的一线治疗。然而，当索拉非尼被证明不够时，需要更有效的替代品。在这项研究中，我们的目标是设计一种超越索拉非尼功效的结构，使我们首次合成索拉非尼-钌络合物并研究其特性。我们的结果表明，与单独的索拉非尼相比，索拉非尼-钌复合物表现出更好的表皮生长因子受体（EGFR）抑制作用。有趣的是，在这些复合物中，Ru3S对各种癌细胞系（包括索拉非尼耐药的 HepG2 细胞）表现出高活性，同时在健康细胞系中表现出明显低于索拉非尼的细胞毒性。细胞周期、细胞凋亡和抗血管生成作用的进一步评估、分子对接和分子动力学研究表明，Ru3S作为候选药物具有巨大的潜力。此外，当游离Ru3S被封装到聚合物胶束M1中时，观察到对HepG2细胞的细胞毒性增强。总的来说，这些发现使Ru3S成为 EGFR 抑制的有前途的候选者，并值得为药物开发目的进行进一步探索。