期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 140, 期 -, 页码 104-117出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.09.007
关键词
Cyclometalated Ru(II) complexes; beta-carboline alkaloids; Cytotoxicity; Apoptosis; Mitochondrial dysfunction
资金
- National Natural Science Foundation of China [21701034]
- Guangdong Provincial Bureau of traditional Chinese Medicine research foundation [20161143]
- Training Plan of Guangdong Province Outstanding Young Teachers in Higher Education Institutions [YQ201401, YQ2015086]
- Medical Scientific Research Foundation of Guangdong Province of China [A2015500, A2016464, A2017309]
- University Student Innovation Experiment Program [201710571004, 201710571017]
Two new cyclometalated Ru(II) complexes of the general formula [Ru(N-N)(2)(1-Ph-beta C)](PF6), where N-N = 4,4'-dimethyl-2,2'-bipyridine (dmb, Ru1), 2,2'-bipyridine (bpy, Ru2), and 1-Ph-beta C (1-phenyl-9H-pyrido[3,4-b]indole) is a beta-carboline alkaloids derivatives, have been synthesized and characterized. The in vitro cytotoxicities, cellular uptake and localization, cell cycle arrest and apoptosis-inducing mechanisms of these complexes have been extensively explored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, inductively coupled plasma mass spectrometry (ICP-MS), flow cytometry, comet assay, inverted fluorescence microscope as well as western blotting experimental techniques. Notably, Ru1 and Ru2 exhibit potent antiproliferative activities against selected human cancer cell lines with IC50 values lower than those of cisplatin and other non-cyclometalated Ru(II) beta-carboline complexes. The cellular uptake and localization exhibit that these complexes can accumulate in the cell nuclei. Further antitumor mechanism studies show that Ru1 and Ru2 can cause cell cycle arrest in the G0/G1 phase by regulating cell cycle relative proteins and induce apoptosis through mitochondrial dysfunction, reactive oxygen species (ROS) accumulation and ROS-mediated DNA damage. (C) 2017 Elsevier Masson SAS. All rights reserved.
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