Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin , James's Street, Dublin 8, Dublin, Ireland.
A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School , 149 13th Street, Suite 2301, Charlestown, Massachusetts 02129, United States.
J Am Chem Soc. 2017 Oct 11;139(40):14302-14314. doi: 10.1021/jacs.7b08640. Epub 2017 Sep 26.
Seven rhenium(I) complexes of the general formula fac-[Re(CO)(NN)(OH)] where NN = 2,2'-bipyridine (8), 4,4'-dimethyl-2,2'-bipyridine (9), 4,4'-dimethoxy-2,2'-bipyridine (10), dimethyl 2,2'-bipyridine-4,4'-dicarboxylate (11), 1,10-phenanthroline (12), 2,9-dimethyl-1,10-phenanthroline (13), or 4,7-diphenyl-1,10-phenanthroline (14), were synthesized and characterized by H NMR spectroscopy, IR spectroscopy, mass spectrometry, and X-ray crystallography. With the exception of 11, all complexes exhibited 50% growth inhibitory concentration (IC) values that were less than 20 μM in HeLa cells, indicating that these compounds represent a new potential class of anticancer agents. Complexes 9, 10, and 13 were as effective in cisplatin-resistant cells as wild-type cells, signifying that they circumvent cisplatin resistance. The mechanism of action of the most potent complex, 13, was explored further by leveraging its intrinsic luminescence properties to determine its intracellular localization. These studies indicated that 13 induces cytoplasmic vacuolization that is lysosomal in nature. Additional in vitro assays indicated that 13 induces cell death without causing an increase in intracellular reactive oxygen species or depolarization of the mitochondrial membrane potential. Further studies revealed that the mode of cell death does not fall into one of the canonical categories such as apoptosis, necrosis, paraptosis, and autophagy, suggesting that a novel mode of action may be operative for this class of rhenium compounds. The in vivo biodistribution and metabolism of complex 13 and its Tc analogue 13* were also evaluated in naı̈ve mice. Complexes 13 and 13* exhibited comparable biodistribution profiles with both hepatic and renal excretion. High-performance liquid chromatography inductively coupled plasma mass-spectrometry (HPLC-ICP-MS) analysis of mouse blood plasma and urine postadministration showed considerable metabolic stability of 13, rendering this potent complex suitable for in vivo applications. These studies have shown the biological properties of this class of compounds and demonstrated their potential as promising theranostic anticancer agents that can circumvent cisplatin resistance.
七种铼（I）配合物的通式为 fac-[Re(CO)(NN)(OH)]，其中 NN = 2,2'-联吡啶（8）、4,4'-二甲基-2,2'-联吡啶（9）、4,4'-二甲氧基-2,2'-联吡啶（10）、二甲基 2,2'-联吡啶-4,4'-二羧酸酯（11）、1,10-菲咯啉（12）、2,9-二甲基-1,10-菲咯啉（13）或 4,7-二苯基-1,10-菲咯啉（14）。这些配合物均通过 H NMR 光谱、IR 光谱、质谱和 X 射线晶体学进行了合成和表征。除了 11 之外，所有配合物在 HeLa 细胞中的 50%生长抑制浓度（IC）值均小于 20 μM，表明这些化合物代表了一类新的潜在抗癌药物。配合物 9、10 和 13 在顺铂耐药细胞中的作用与野生型细胞一样有效，表明它们规避了顺铂耐药性。通过利用其内在的发光性质来确定其细胞内定位，进一步研究了最有效的配合物 13 的作用机制。这些研究表明，13 诱导细胞质空泡化，其本质是溶酶体。此外，体外实验表明，13 诱导细胞死亡而不会导致细胞内活性氧增加或线粒体膜电位去极化。进一步的研究表明，细胞死亡的模式不属于凋亡、坏死、paraptosis 或自噬等典型类别之一，这表明该类铼化合物可能具有一种新的作用模式。还在未经处理的小鼠中评估了配合物 13 和其 Tc 类似物 13的体内分布和代谢。配合物 13 和 13 表现出相似的体内分布特征，均具有肝和肾排泄。给药后小鼠血浆和尿液的高效液相色谱电感耦合等离子体质谱（HPLC-ICP-MS）分析显示，13 的代谢稳定性相当高，这使得该有效配合物适合于体内应用。这些研究展示了该类化合物的生物学特性，并证明了它们作为有前途的治疗性抗癌药物的潜力，可以规避顺铂耐药性。
