Iron-Catalyzed Synthesis of Ferrocenyl–Thioether Conjugates via C–S Cross-Coupling of Thioethers and Vinylic Chlorides: Construction, Anticancer, and Computational Studies

Herein, a library of ferrocenyl–thioether derivatives of acrylaldehyde and acrylonitrile is developed via a direct C–S bond formation reaction under mild conditions. Various aromatic and aliphatic thiols were successfully coupled with ferrocenyl acrylaldehyde/acrylonitrile in the presence of a chalcogen-stabilized iron–carbonyl cluster (Fe3Se2(CO)9). All the reactions were carried out in water under aerobic conditions, and the transformation of a wide range of ferrocenyl–thioether derivatives in good yields were obtained. Furthermore, cytotoxicity studies of some selected ferrocenyl–thioethers were performed against the prostate cancer cell line (PC-3) and normal human embryonic kidney cell line (HEK). 3-Ferrocenyl-3-(4-trifluoromethyl)-phenylsulfanyl was found to be significantly active. It showed an IC50 of 5.5 μM toward prostate cancer cell lines. Moreover, it also showed activity comparable to that of standard anticancer drugs including axitinib, nelfinavir, thymitaq, and (±) thioridazine. The anticancer activity was further supported by density functional theory calculations including the HOMO–LUMO energy gap, cyclic voltammetry, UV–vis studies, molecular docking, and reactive oxygen species analysis. All compounds synthesized in this report are new, and they may serve as milestones in the futuristic research of anticancer drugs.本研究通过温和条件下的直接碳硫键形成反应，构建了一类丙烯醛与丙烯腈的二茂铁基硫醚衍生物库。各类芳香族及脂肪族硫醇均可在硫族稳定的铁羰基簇（chalcogen-stabilized iron–carbonyl cluster, Fe₃Se₂(CO)₉）的介导下，与二茂铁基丙烯醛/丙烯腈顺利发生偶联反应。所有反应均在水相有氧环境中进行，最终以良好产率得到了一系列结构多样的二茂铁基硫醚衍生物。此外，本研究针对部分筛选得到的二茂铁基硫醚衍生物，开展了针对前列腺癌细胞系（PC-3）与正常人胚肾细胞系（HEK）的细胞毒性实验。其中，3-二茂铁基-3-(4-三氟甲基)苯硫基化合物展现出显著的抗癌活性：其对前列腺癌细胞系的半抑制浓度（IC₅₀）为5.5 μM。进一步研究表明，该化合物的抗癌活性可与阿昔替尼（axitinib）、奈非那韦（nelfinavir）、替米他奎（thymitaq）以及(±)硫利达嗪（(±) thioridazine）等标准抗癌药物相当。本研究还通过密度泛函理论计算（含HOMO-LUMO能隙分析）、循环伏安法、紫外-可见光谱研究、分子对接以及活性氧分析等多种手段，进一步验证了该类化合物的抗癌活性。本报告中合成的所有化合物均为新型衍生物，有望成为未来抗癌药物研究领域的重要里程碑。