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寻找新的具有生物活性的化合物:二钌(II,II)桨轮配合物的抗肿瘤和抗菌活性研究。

Search for new biologically active compounds: studies of antitumor and antimicrobial activity of dirhodium(II,II) paddlewheel complexes.

机构信息

University of Kragujevac, Faculty of Medical Sciences, Department of Medical Biochemistry, Svetozara Markovića 69, 34000 Kragujevac, Serbia.

University of Kragujevac, Faculty of Science, Department of Chemistry, Radoja Domanovića 12, 34000 Kragujevac, Serbia.

出版信息

Dalton Trans. 2024 Jun 4;53(22):9330-9349. doi: 10.1039/d4dt01082e.

Abstract

Four neutral Rh1-Rh4 complexes of the general formula [Rh(CHCOO)L], where L is an -alkylimidazole ligand, were synthesized and characterized using various spectroscopic techniques, and in the case of Rh4 the crystal structure was confirmed. Investigation of the interactions of these complexes with HSA by fluorescence spectroscopy revealed that the binding constants are moderately strong (∼10 M), and site-marker competition experiments showed that the complexes bind to Heme site III (subdomain IB). Competitive binding studies for CT DNA using EB and HOE showed that the complexes bind to the minor groove, which was also confirmed by viscosity experiments. Molecular docking confirmed the experimental data for HSA and CT DNA. Antimicrobial tests showed that the Rh2-Rh4 complexes exerted a strong inhibitory effect on G bacteria and G bacteria as well as on the yeast , which showed a higher sensitivity compared to fluconazole. The cytotoxic activity of Rh1-Rh4 complexes tested on three cancer cell lines (HeLa, HCT116 and MDA-MB-231) and on healthy MRC-5 cells showed that all investigated complexes elicited more efficient cytotoxicity on all tested tumor cells than on control cells. Investigation of the mechanism of action revealed that the Rh1-Rh4 complexes inhibit cell proliferation different mechanisms of action, namely apoptosis (increase in expression of the pro-apoptotic Bax protein and caspase-3 protein in HeLa and HCT116 cells; changes in mitochondrial potential and mitochondrial damage; release of cytochrome c from the mitochondria; cell cycle arrest in G2/M phase in both HeLa and HCT116 cells together with a decrease in the expression of cyclin A and cyclin B) and autophagy (reduction in the expression of the protein p62 in HeLa and HCT116 cells).

摘要

合成并采用多种光谱技术表征了[Rh(CHCOO)L](其中 L 为 - 烷基咪唑配体)的四个中性 Rh1-Rh4 配合物,其中 Rh4 的晶体结构得到了确证。荧光光谱法研究了这些配合物与 HSA 的相互作用,结果表明结合常数为中等强度(约 10 M),位点标记竞争实验表明配合物结合到 Heme 位点 III(亚域 IB)。使用 EB 和 HOE 对 CT DNA 进行的竞争性结合研究表明,配合物结合到小沟,这也通过粘度实验得到了证实。分子对接证实了与 HSA 和 CT DNA 的实验数据相符。抗菌试验表明,Rh2-Rh4 配合物对 G 细菌和 G 细菌以及酵母表现出很强的抑制作用,与氟康唑相比,显示出更高的敏感性。在三种癌细胞系(HeLa、HCT116 和 MDA-MB-231)和健康 MRC-5 细胞上测试 Rh1-Rh4 配合物的细胞毒性活性表明,所有研究的配合物对所有测试的肿瘤细胞的细胞毒性都比对照细胞更有效。作用机制的研究表明,Rh1-Rh4 配合物通过不同的作用机制抑制细胞增殖,即凋亡(在 HeLa 和 HCT116 细胞中,促凋亡 Bax 蛋白和 caspase-3 蛋白的表达增加;线粒体膜电位和线粒体损伤的变化;细胞色素 c 从线粒体释放;HeLa 和 HCT116 细胞的细胞周期停滞在 G2/M 期,同时 cyclin A 和 cyclin B 的表达减少)和自噬(HeLa 和 HCT116 细胞中 p62 蛋白表达减少)。

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