Cyanide Decorporation by Co(III) Schiff-base Macrocycles

Co(III) 希夫碱大环化合物的氰化物修饰

• 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
• 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

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）：根据过去通过烟雾吸入的气态HCN中毒的经验，很明显，许多可治疗的个体（大规模伤亡）在暴露30分钟后仍会出现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，但它远非理想和昂贵。我们最近已经证明了一种含钴（III）的水溶性卟啉，表现出更好的氰化物结合能力