Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, Guangdong 524023, PR China.
Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China.
J Inorg Biochem. 2023 Sep;246:112295. doi: 10.1016/j.jinorgbio.2023.112295. Epub 2023 Jun 15.
Two new ruthenium(II) complexes [Ru(dip)(PPβC)]PF (Ru1, dip = 4,7-diphenyl-1,10-phenanthroline, PPβC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide) and [Ru(phen)(PPβC)]PF (Ru2, phen = 1, 10-phenanthroline) with β-carboline derivative PPβC as the primary ligand, were designed and synthesized. Ru1 and Ru2 displayed higher antiproliferative activity than cisplatin against the test cancer cells, with IC values ranging from 0.5 to 3.6 μM. Moreover, Ru1 and Ru2 preferentially accumulated in mitochondria and caused a series of changes in mitochondrial events, including the depolarization of mitochondrial membrane potential, the damage of mitochondrial DNA, the depletion of cellular ATP, and the elevation of intracellular reactive oxygen species levels. Then, it induced caspase-3/7-mediated A549 cell apoptosis. More importantly, both complexes could act as topoisomerase I catalytic inhibitors to inhibit mitochondrial DNA synthesis. Accordingly, the developed Ru(II) complexes hold great potential to be developed as novel therapeutics for cancer treatment.
两个新的钌（II）配合物[Ru(dip)(PPβC)]PF（Ru1，dip=4,7-二苯基-1,10-菲咯啉，PPβC=N-(1,10-菲咯啉-5-基)-1-苯基-9H-吡啶并[3,4-b]吲哚-3-甲酰胺）和[Ru(phen)(PPβC)]PF（Ru2，phen=1,10-菲咯啉），以β-咔啉衍生物 PPβC 作为主要配体，被设计和合成。Ru1 和 Ru2 对测试癌细胞的增殖活性比顺铂高，IC 值范围为 0.5 至 3.6μM。此外，Ru1 和 Ru2 优先积聚在线粒体中，并引起一系列线粒体事件的变化，包括线粒体膜电位去极化、线粒体 DNA 损伤、细胞内 ATP 耗竭和细胞内活性氧水平升高。然后，它诱导 caspase-3/7 介导的 A549 细胞凋亡。更重要的是，这两个配合物都可以作为拓扑异构酶 I 催化抑制剂来抑制线粒体 DNA 的合成。因此，所开发的 Ru(II) 配合物具有很大的潜力，可以开发为癌症治疗的新型治疗剂。
