Design, Synthesis, DNA/HSA Binding, and Cytotoxic Activity of Half-Sandwich Ru(II)-Arene Complexes Containing Triarylamine–Thiosemicarbazone Hybrids

Organoruthenium complexes are potent
alternatives for platinum-based
complexes because of their superior anticancer activity. In this investigation,
a series of new Ru­(II)-arene complexes with triarylamine–thiosemicarbazone
hybrid ligands with higher anticancer activity than cisplatin are
reported. The molecular structure of the ligands and complexes was
confirmed spectroscopically and supported by single-crystal X-ray
crystallography. These complexes adopted a three-leg piano stool geometry.
All the Ru­(II)-arene complexes were systematically investigated for
their in vitro cytotoxicity against human cervical (HeLa S3), lung
(A549) cancer, and human normal lung (IMR-90) cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide assay. Interestingly, a pyrrolidine-attached Ru­(II)-benzene
complex exhibited superior activity against cancer cells with low
IC50 values, and colony formation study showed complete
inhibition at 5 and 10 μM concentration. Furthermore, morphological
changes assessed by acridine orange and propidium iodide staining
revealed that the cell death occurred by apoptosis. In addition, the
interaction between synthesized Ru­(II)-arene complexes and DNA/protein
was explored by absorption and emission spectroscopy methods. These
synthesized new organoruthenium complexes can be used for developing
new metal-based anticancer drugs.

有机钌配合物（Organoruthenium complexes）因其优异的抗癌活性，是铂类配合物（platinum-based complexes）极具潜力的替代候选物。本研究报道了一系列基于三芳胺-硫代半卡巴腙杂合配体（triarylamine–thiosemicarbazone hybrid ligands）的新型钌(II)-芳烃配合物（Ru(II)-arene complexes），其抗癌活性优于顺铂（cisplatin）。通过光谱法对配体及配合物的分子结构进行了确证，并通过单晶X射线衍射分析（single-crystal X-ray crystallography）予以佐证。此类配合物均采用三脚钢琴凳构型（three-leg piano stool geometry）。采用溴化3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑比色法（3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay，简称MTT法），系统评价了所有钌(II)-芳烃配合物对人体宫颈癌细胞（HeLa S3）、肺癌细胞（A549）以及人体正常肺细胞（IMR-90）的体外细胞毒性（in vitro cytotoxicity）。值得注意的是，连有吡咯烷基团的钌(II)-苯配合物对癌细胞展现出更优的活性，其半抑制浓度（IC50）极低；集落形成实验（colony formation study）结果显示，在5 μM和10 μM浓度下即可完全抑制癌细胞集落形成。进一步通过吖啶橙（acridine orange）与碘化丙啶（propidium iodide）双染色法评估细胞形态变化，结果表明细胞死亡途径为细胞凋亡（apoptosis）。此外，通过吸收光谱与发射光谱法（absorption and emission spectroscopy）探究了所合成的钌(II)-芳烃配合物与脱氧核糖核酸（DNA）及蛋白质（protein）的相互作用。本研究合成的新型有机钌配合物可用于开发新一代金属基抗癌药物。