Positively-charged, chalcone-hydroxypyrone hybrid ruthenium(II)-arene complexes functionalized with ethacrynic acid: Synthesis, characterizaion, and antitumor effect

IF 3.8 2区 化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yuxin Xuan , Yuxi Yan , Xiaonan Wei, Shuxiang Wang, Jinchao Zhang, Yonghe Tang, Shenghui Li
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Abstract

A new family of ethacrynic acid-functionalized, chalcone-hydroxypyrone hybrid ruthenium(II)-arene complexes (4a-4e) have been designed, synthesis and fully characterized by 1H and 13C NMR, ESI-MS, elemental analysis, and melting point tests. The molecular structure of 3a, one of the precursor complexes, has been determined by single-crystal X-ray diffraction. The cytotoxicity of the obtained complexes toward human cancer cell lines such as HeLa, MGC803, A549, MDA-MB-231, and MCF-7 cells have been investigated by MTT assay. Whereas complexes 4d and 4e showed significantly higher cytotoxicity than cisplatin (the positive control group) and complexes 3a-3e. Moreover, complexes 4d and 4e exhibited a certain selectivity (selectivity index: 7.33 and 7.57) toward MCF-7 cells over MCF-10a normal cells. Glutathione S-transferases (GSTs) activity assay indicate that complexes 4d and 4e exhibited higher GST inhibitory activity than ethacrynic acid (EA, the best characterized GST inhibitor), consistent with their higher cytotoxicity. Further mechanistic studies showed that 4e-induced cell apoptosis may be aroused by the production of ROS, the loss of mitochondrial membrane potential and G2/M phase cell arrest in MCF-7 cells. In addition, the in vivo antitumor effect study on the xenograft mouse models of MCF-7 cells reveal that complex 4e significantly inhibited tumor growth with a higher inhibition efficiency of 68.80 %, in comparison with the groups treated with cisplatin (59.25 %). These results highlight the strong possibility to develop positively-charged, chalcone-hydroxypyrone hybrid ruthenium(II)-arene complexes funcionalized with GST inhibitor as promising anticancer agents.

Abstract Image

带正电的查尔酮-羟吡啶杂化钌(II)-芳烃配合物的合成、表征及抗肿瘤作用
设计、合成了一类新的乙炔酸功能化的查尔酮-羟基吡啶杂化钌(II)-芳烃配合物(4a-4e),并通过1H和13C NMR、ESI-MS、元素分析和熔点测试对其进行了全面表征。用单晶x射线衍射测定了前驱物之一3a的分子结构。用MTT法研究了所获得的复合物对HeLa、MGC803、A549、MDA-MB-231和MCF-7等人癌细胞的细胞毒性。而配合物4d和4e的细胞毒性明显高于顺铂(阳性对照组)和配合物3a-3e。复合物4d和4e对MCF-7细胞比MCF-10a正常细胞具有一定的选择性(选择性指数分别为7.33和7.57)。谷胱甘肽s -转移酶(GSTs)活性测定表明,配合物4d和4e比乙酸(EA,表征最好的GST抑制剂)具有更高的GST抑制活性,与它们更高的细胞毒性一致。进一步的机制研究表明,4e诱导的MCF-7细胞凋亡可能与ROS的产生、线粒体膜电位的丧失和G2/M期细胞阻滞有关。此外,对MCF-7细胞异种移植小鼠模型的体内抗肿瘤作用研究表明,复合物4e显著抑制肿瘤生长,抑制效率为68.80%,高于顺铂组(59.25%)。这些结果强调了开发与GST抑制剂功能化的带正电荷的查尔酮-羟基吡啶杂化钌(II)-芳烃配合物作为抗癌药物的可能性。
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来源期刊
Journal of Inorganic Biochemistry
Journal of Inorganic Biochemistry 生物-生化与分子生物学
CiteScore
7.00
自引率
10.30%
发文量
336
审稿时长
41 days
期刊介绍: The Journal of Inorganic Biochemistry is an established international forum for research in all aspects of Biological Inorganic Chemistry. Original papers of a high scientific level are published in the form of Articles (full length papers), Short Communications, Focused Reviews and Bioinorganic Methods. Topics include: the chemistry, structure and function of metalloenzymes; the interaction of inorganic ions and molecules with proteins and nucleic acids; the synthesis and properties of coordination complexes of biological interest including both structural and functional model systems; the function of metal- containing systems in the regulation of gene expression; the role of metals in medicine; the application of spectroscopic methods to determine the structure of metallobiomolecules; the preparation and characterization of metal-based biomaterials; and related systems. The emphasis of the Journal is on the structure and mechanism of action of metallobiomolecules.
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