羰基钌一氧化碳释放分子的合成、毒理、分布及代谢研究

发布时间：2018-04-12 00:03

本文选题：羰基钌 + 一氧化碳释放分子　；参考：《兰州大学》2014年硕士论文

【摘要】：一氧化碳是类似于NO的信号传递分子,而功能化的羰基金属化合物是CO分子的固载形式。大量的体内外活性实验表明,羰基钌CO释放分子具有预期的内源性CO的生理作用,在多种药物模型中表现出良好的药理活性,诸如扩张血管、抗炎、抑制细胞凋亡及器官移植排斥反应等。然而这种外源性的羰基金属CO释放分子的毒理学性质和体内代谢动力学过程,特别是体内分布和代谢途径,是决定该类物质能否成为临床前药物的关键,本论文在全面总结羰基金属化合物文献的基础上,合成、表征了15个羰基钌CORMs,并从细胞毒性、体内毒性、组织分布及代谢途径等多个方面对其进行了研究,主要包括以下几个方面： 1)利用肌红蛋白转化为羰基肌红蛋白的原理,应用紫外分光光度法测试了所有目标分子的CO释放能力,其半衰期为1.0-15.8min;同时用正辛醇-磷酸缓冲液体系测试了所有目标分子的脂水分配系数,其logP值为-1.59-1.13。 2)毒性实验：MTT法检测显示目标分子1-15对成纤维细胞没有明显的生长抑制作用,IC50介于67-2089μM范围；小鼠经口急性毒性实验结果表明,大部分化合物LDso介于800-1500mg/kg；大鼠连续给药后,经透射电镜检查,实验动物肝肾组织细胞出现核固缩、畸形、线粒体扩张等形态异常现象。 3)体内分布：以ICP-AES为检测手段分析显示,该类化合物主要分布于血液、肝脏及肾脏组织,其他组织中分布较少,且不能透过血脑屏障。 4)代谢：通过ESI-MS、FT-IR及XPS等多种手段对该类化合物的体内进程进行跟踪发现,羰基钌CO释放分子在体内代谢过程中羰基是逐步释放的,尿液代谢产物中不含有羰基；XPS检测显示其代谢物中金属主要以钌m配位化合物形式经尿液排出。
[Abstract]:Carbon monoxide is a signaling molecule similar to no, while the functional carbonyl metal compounds are the form of CO immobilization.A large number of experiments in vivo and in vitro showed that carbonyl ruthenium CO releasing molecules had the expected physiological effect of endogenous CO and showed good pharmacological activities in many drug models, such as vasodilation, anti-inflammation, and so on.Inhibition of apoptosis and rejection of organ transplantation.However, the toxicological properties and metabolic kinetics of the exogenous carbonyl metal CO releasing molecules, especially the distribution and metabolic pathways in vivo, are the key factors to determine whether these compounds can be used as preclinical drugs.On the basis of summarizing the literature of carbonyl metal compounds, 15 carbonyl ruthenium Corms were synthesized and characterized, and their cytotoxicity, in vivo toxicity, tissue distribution and metabolic pathway were studied.It mainly includes the following aspects:1) based on the principle of converting myoglobin into carbonyl myoglobin, the CO release ability of all target molecules was measured by ultraviolet spectrophotometry.The half-life was 1.0-15.8 min, and the lipids and water partition coefficients of all target molecules were measured by n-octanol-phosphate buffer system with logP values of -1.59-1.13.2) the cytotoxicity test showed that the target molecule 1-15 had no obvious inhibitory effect on fibroblast growth and IC50 was between 67-2089 渭 M. the results of acute toxicity test in mice showed that most of the compounds LDso were between 800-1500 mg / kg, and after continuous administration in rats, most of the compounds were between 800-1500mg / kg.The morphologic abnormalities of liver and kidney tissue cells were observed by transmission electron microscope (TEM), such as nuclear shrinkage, deformity and mitochondrial dilatation.3) in vivo distribution: the analysis of ICP-AES showed that the compounds were mainly distributed in blood, liver and kidney, but less in other tissues, and could not penetrate the blood-brain barrier.4) Metabolism: by means of ESI-MSFT-IR and XPS, it was found that carbonyl ruthenium CO releasing molecules were gradually released in vivo.The results of XPS analysis showed that the metal in the metabolites was mainly excreted by urine in the form of ruthenium m coordination compounds.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5;R965

【共引文献】