Cyanide Decorporation by Co(III) Schiff-base Macrocycles

Co(III) 希夫碱大环化合物的氰化物修饰

基本信息

批准号：
8793566
负责人：
LINDA L PEARCE
金额：
$ 36.31万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8793566
关键词：
Acids Acute Adolescent Adult Affinity Air Animal Testing Animals Antidotes Behavior assessment Behavioral Assay Binding Biological Blood Circulation Cardiac Cessation of life Characteristics Clinic Cobalamin Cobalt Complex Control Animal Corrinoids Cyanides Development Dose Effectiveness Electron Spin Resonance Spectroscopy Electronics Emergency Situation Equilibrium Euthanasia Exhibits FDA approved Female Geometry Hydrogen Sulfide Impairment Individual Inhalation Exposure Intoxication Ions Label Ligands Literature Measurement Measures Metalloporphyrins Metals Mining Monitor Mus Musculoskeletal Neurologic Nitrogen Poisoning Porphyrins Positioning Attribute Procedures Production Puncture procedure Reaction Recovery Reporting Rotarod Performance Test Salts Schiff Bases Solubility Spectrophotometry Structure System Testing Time Titrations Toxic effect Toxin Triage Water Weight Whole Blood absorption biophysical properties circular magnetic dichroism cobinamide dalton experience foot improved knock-down mass casualty oxidation pregnant prevent public health relevance research study smoke inhalation weapons

项目摘要

DESCRIPTION (provided by applicant): Drawing on past experience of gaseous HCN poisoning through smoke inhalation, it is clear that many treatable individuals (mass casualties) will present at triage more than 30 min after exposure still exhibiting signs of acute cyanide toxicity. Compounds that lower the circulating level of free cyanide in the bloodstream have been shown to be effective antidotes to cyanide poisoning in such cases. Cobalamin is currently the only FDA-approved cyanide-binding coordination compound available as an antidote for emergency and clinic use, but it is far from ideal and expensive. We have very recently shown that a cobalt(III)-containing water-soluble porphyrin, exhibiting better cyanide-binding capability than cobalamin, functions as a cyanide antidote in mice [Benz et al (2012) Chem Res Tox, 25, 2678-86]. We hypothesize that many compounds in which cobalt(III) is surrounded by a square-planar arrangement of nitrogen-donors with two labile ligands in the axial positions are good candidate antidotes for cyanide (and hydrogen sulfide) poisoning. The syntheses of numerous simpler (less expensive) complexes of cobalt(III) having this necessary surrounding ligand geometry have been reported and many more are accessible by trivial derivatization of compounds reported in the existing inorganic literature. Macrocyclic complexes, in which the cobalt(III) ion is retained by a chelate ring, are expected to be non-toxic at the levels required o be efficacious in treating cyanide intoxication. Aim 1. To synthesize, by exploiting the existing literature, a small number of cobalt(III)-containing Schiff-base macrocycles (3 to 6) and determine the cyanide-binding characteristics of these compounds. Aim 2. To demonstrate that the cobalt(III)-containing Schiff-base macrocycles are effective antidotes to cyanide intoxication in mice. A variety of biophysical measurements and behavioral assays will be used to assess the effectiveness of the candidate compounds as cyanide- scavenging agents.

描述（由申请人提供）：根据过去因吸入烟雾而导致气态 HCN 中毒的经验，很明显，许多可治疗的个体（大规模伤亡人员）在接触后 30 分钟以上在分诊时仍然表现出急性氰化物中毒的迹象。在这种情况下，降低血液中游离氰化物循环水平的化合物已被证明是氰化物中毒的有效解毒剂。钴胺素是目前 FDA 批准的唯一一种可用作紧急和临床使用解毒剂的氰化物结合配位化合物，但它远非理想且昂贵。我们最近发现一种含钴（III）的水溶性卟啉，具有更好的氰化物结合能力比钴胺素更有效，在小鼠体内可作为氰化物解毒剂 [Benz et al (2012) Chem Res Tox, 25, 2678-86]。我们假设许多化合物，其中钴（III）被方形平面排列的氮供体包围，在轴向位置有两个不稳定配体，是氰化物（和硫化氢）中毒的良好候选解毒剂。具有这种必要的周围配体几何形状的许多更简单（更便宜）的钴（III）络合物的合成已经被报道，并且更多的络合物可以通过现有无机文献中报道的化合物的简单衍生化来获得。大环配合物（其中钴（III）离子被螯合环保留）预计在有效治疗氰化物中毒所需的水平下是无毒的。目的 1. 利用现有文献合成少量含钴(III)的希夫碱大环化合物（3至6个）并确定这些化合物的氰化物结合特性。目标 2. 证明含钴 (III) 席夫碱大环化合物是小鼠氰化物中毒的有效解毒剂。将使用各种生物物理测量和行为测定来评估候选化合物作为氰化物清除剂的有效性。