Wang Peng-peng, Liu Hua-peng, Zhao Quan-yi, Chen Yong-lin, Liu Bin, Zhang Bao-ping, Zheng Qian
Institute of Medicinal Chemistry, School of Pharmacy, Lanzhou University, China.
The First Hospital of Lanzhou University, China.
Yao Xue Xue Bao. 2013 Nov;48(11):1677-87.
Carbon monoxide has been proved to be an important signal molecule in body. Transition metal carbonyl compounds are solidified form of carbon monoxide. Numerous studies have shown that Ruthenium carbonyl carbon monoxide releasing molecules have a strong pharmacological activity. In this paper, five Ruthenium (II) carbonyl CORMs 1-5 were synthesized and their toxicology, tissue distribution and interaction with blood endogenous substances were investigated. The results showed CORMs' IC50 to fibroblasts are ranged from 212.9 to 2089.2 micromol x L(-1). Their oral LD50 to mouse is between 800 to 1600 mg x kg(-1). After repeated administration, CORMs 1 and CORMs 5 haven't shown an obvious influence to rats' liver and kidney function, but caused the injury to liver and kidney cells. The in vivo distribution result revealed the majority of CORMs were distributed in blood, liver and kidney, only a small part of CORMs distributed in lung, heart and spleen. They could scarcely cross the blood-brain barrier and distribute to brain. The non-CO ligands in structure have an obvious relevance to their in vivo absorption and distribution. Interestingly, CORMs could enhance the fluorescence of bovine serum albumin, and this enhancement was in direct proportion with the concentration of CORMs. Under different conditions, interaction of CORMs with glutathione got different type of products, one is Ruthenium (II) tricarbonyl complexes, and Ruthenium (II) dicarbonyl complexes.
一氧化碳已被证明是体内一种重要的信号分子。过渡金属羰基化合物是一氧化碳的固化形式。大量研究表明，钌羰基一氧化碳释放分子具有很强的药理活性。本文合成了五种钌（II）羰基一氧化碳释放分子（CORMs）1-5，并对其毒理学、组织分布以及与血液内源性物质的相互作用进行了研究。结果表明，CORMs对成纤维细胞的半数抑制浓度（IC50）在212.9至2089.2微摩尔/升之间。它们对小鼠的经口半数致死剂量（LD50）在800至1600毫克/千克之间。重复给药后，CORMs 1和CORMs 5对大鼠的肝肾功能未显示出明显影响，但导致了肝细胞和肾细胞的损伤。体内分布结果显示，大部分CORMs分布在血液、肝脏和肾脏中，只有一小部分分布在肺、心脏和脾脏中。它们几乎不能穿过血脑屏障并分布到大脑。结构中的非CO配体与其体内吸收和分布有明显相关性。有趣的是，CORMs可以增强牛血清白蛋白的荧光，且这种增强与CORMs的浓度成正比。在不同条件下，CORMs与谷胱甘肽相互作用会得到不同类型的产物，一种是钌（II）三羰基配合物，另一种是钌（II）二羰基配合物。
