Cyanide Decorporation by Co(III) Schiff-base Macrocycles

描述(由申请人提供)：根据过去通过烟雾吸入引起的气态HCN中毒的经验，很明显，许多可治疗的个人(大量伤亡)在暴露后30分钟以上的分诊时仍显示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有效的氰化物中毒解毒剂。钴胺目前是FDA批准的唯一一种氰化物结合的配位化合物，可用作紧急和临床解毒剂，但它远不理想，也很昂贵。我们最近发现了一种含钴(III)的水溶性卟啉，表现出更好的氰化物结合能力 与钴胺相比，它在小鼠中具有氰化物解毒剂的作用[Benz等人(2012)Chem res Tox，25,2678-86]。我们假设，许多钴(III)被正方形平面排列的氮供体包围的化合物是氰化物(和硫化氢)中毒的很好的候选解毒剂。已有报道合成了许多更简单(不太昂贵)的钴(III)配合物，它们具有这种必需的周围配体构型，更多的化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。大环络合物中的钴(III)离子被一个螯合环保留，预计在有效治疗氰化物中毒所需的水平上是无毒的。目的1.利用已有文献合成少量含钴(III)席夫碱大环(3~6个)，并测定这些化合物的氰化物结合特性。目的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分析来评估候选化合物作为氰化物清除剂的有效性。

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.