Investigation of Cobalt(III) Cage Complexes as Inhibitors of the Mitochondrial Calcium Uniporter
Investigation of Cobalt(III) Cage Complexes as Inhibitors of the Mitochondrial Calcium Uniporter
复制标题
钴(III)笼复合物作为线粒体钙单向转运蛋白抑制剂的研究
DOI：
10.1002/ejic.202200735
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发表时间：
2023
影响因子：
2.3
通讯作者：
Wilson, Justin J.
中科院分区：
文献类型：
--
作者：
Bigham, Nicholas P.;Wilson, Justin J.
线粒体钙单转运体（MCU）介导钙离子（Ca2+）进入线粒体，这一过程对维持正常细胞功能至关重要。MCU抑制剂，其中最有前途的是双核钌配位化合物，已被发现作为治疗剂和研究该离子通道重要性的工具。在这项研究中，研究人员评估了六种具有石棺碱样配体的Co3+笼化合物抑制MCU介导的线粒体Ca2+摄取的能力。根据文献程序合成并表征了这些复合物，然后在细胞系统中研究了它们的MCU抑制活性。其中，[Co(sen)]3+（3,sen =5‐（4‐氨基‐2‐氮杂丁基）‐5‐甲基‐3,7‐氮杂‐1,9‐壬二胺）被鉴定为有效的MCU抑制剂，对HeLa和HEK293T细胞的抑制作用分别为160 nM和180 nM， ic50值。此外，测定了化合物3的细胞摄取，显示其在细胞中有适度的积累。最值得注意的是，3被证明在完整细胞中作为MCU抑制剂起作用。总之，本研究提出了钴配合物作为MCU抑制剂的可行性，为研究人员提供了新的研究方向。
The mitochondrial calcium uniporter (MCU) mediates uptake of calcium ions (Ca2+) into the mitochondria, a process that is vital for maintaining normal cellular function. Inhibitors of the MCU, the most promising of which are dinuclear ruthenium coordination compounds, have found use as both therapeutic agents and tools for studying the importance of this ion channel. In this study, six Co3+cage compounds with sarcophagine‐like ligands were assessed for their abilities to inhibit MCU‐mediated mitochondrial Ca2+uptake. These complexes were synthesized and characterized according to literature procedures and then investigated in cellular systems for their MCU‐inhibitory activities. Among these six compounds, [Co(sen)]3+(3, sen=5‐(4‐amino‐2‐azabutyl)‐5‐methyl‐3,7‐diaza‐1,9‐nonanediamine) was identified to be a potent MCU inhibitor, with IC50values of inhibition of 160 and 180 nM in permeabilized HeLa and HEK293T cells, respectively. Furthermore, the cellular uptake of compound3was determined, revealing moderate accumulation in cells. Most notably,3was demonstrated to operate in intact cells as an MCU inhibitor. Collectively, this work presents the viability of using cobalt coordination complexes as MCU inhibitors, providing a new direction for researchers to investigate.