血清稳定的金（III）双膦配合物诱导三阴性乳腺癌中温和的线粒体解偶联和体内抗肿瘤效力。
Serum-Stable Gold(III) Bisphosphine Complex Induces Mild Mitochondrial Uncoupling and In Vivo Antitumor Potency in Triple Negative Breast Cancer.
机构信息
Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506, United States.
Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky 40536, United States.
出版信息
J Med Chem. 2023 Jun 22;66(12):7868-7879. doi: 10.1021/acs.jmedchem.3c00238. Epub 2023 Jun 6.
Abstract
The preparation of cyclometalated complexes offers a path to stable materials, catalysts, and therapeutic agents. Here, we explore the anticancer potential of novel biphenyl organogold(III) cationic complexes supported by diverse bisphosphine ligands, , toward aggressive glioblastoma and triple negative breast cancer cells (TNBCs). The [C^C] gold(III) complex, , exhibits significant tumor growth inhibition in a metastatic TNBC mouse model. Remarkably, displays promising blood serum stability over a relevant therapeutic window of 24 h and alteration in the presence of excess -GSH. The mechanism-of-action studies show that induces mitochondrial uncoupling, membrane depolarization, and G1 cell cycle arrest and prompts apoptosis. To the best of our knowledge, is the first biphenyl gold-phosphine complex to uncouple mitochondria and inhibit TNBC growth in vivo.
摘要
环金属配合物的制备为稳定材料、催化剂和治疗剂提供了一条途径。在这里，我们探索了新型联苯有机金（III）阳离子配合物的抗癌潜力，这些配合物由不同的双膦配体支撑，针对侵袭性神经胶质瘤和三阴性乳腺癌细胞（TNBCs）。[C^C]金（III）配合物，显示出在转移性 TNBC 小鼠模型中显著的肿瘤生长抑制作用。值得注意的是，在相关的 24 小时治疗窗内和存在过量 -GSH 的情况下，表现出良好的血清稳定性。作用机制研究表明，诱导线粒体解偶联、膜去极化和 G1 细胞周期停滞，并促使细胞凋亡。据我们所知，是第一个使线粒体解偶联并抑制体内 TNBC 生长的联苯金-膦配合物。
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