Cyanide Decorporation by Co(III) Schiff-base Macrocycles

描述（由申请人提供）：根据过去通过吸入烟雾引起的气态HCN中毒的经验，很明显，许多可治疗的个体（大规模伤亡）在接触后30分钟仍表现出急性氰化物中毒的体征。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。钴胺素是目前唯一一种FDA批准的氰化物结合配位化合物，可作为紧急和临床使用的解毒剂，但它远非理想且昂贵。我们最近已经表明，一种含钴（III）的水溶性卟啉，表现出更好的氰化物结合能力， 在小鼠中，维生素B1比钴胺素B1更能作为氰化物解毒剂发挥作用[Benz et al（2012）Chem Res Tox，25，2678-86]。我们假设，许多化合物，其中钴（III）是由一个正方形平面排列的氮供体与两个不稳定的配体在轴向位置包围是很好的候选解毒剂氰化物（和硫化氢）中毒。已经报道了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，并且通过现有无机文献中报道的化合物的平凡衍生化可以获得更多。大环络合物，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。目标1.通过利用现有文献合成少量含钴（III）的席夫碱大环化合物（3至6），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。

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.