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.
The release of HCN by acid treatment of cyanide salts is a fairly low-tech potential terrorist weapon that could be devastating in modern buildings and mass transport systems with air re-circulating systems. Cyanide salts are stockpiled throughout the US for manufacturing and mining purposes rendering the possibility of such attacks especially worrisome. Treating inhalation exposures with cyanide-decorporating (-scavenging) agents is a proven therapy, but the presently available (FDA labeled) compound, cobalamin, is a complicated biomolecule that is expensive to produce and does not have particularly high affinity for cyanide. Cognizant of the long-term desirability of easy mass production and stockpiling, we propose to develop a new class of cyanide-decorporating agent that can be synthesized in no more than two steps and requiring only inexpensive starting materials.
|Lopez-Manzano, Elisenda; Cronican, Andrea A; Frawley, Kristin L et al. (2016) Cyanide Scavenging by a Cobalt Schiff-Base Macrocycle: A Cost-Effective Alternative to Corrinoids. Chem Res Toxicol 29:1011-9|
|Benz, Oscar S; Yuan, Quan; Cronican, Andrea A et al. (2016) Effect of Ascorbate on the Cyanide-Scavenging Capability of Cobalt(III) meso-Tetra(4-N-methylpyridyl)porphine Pentaiodide: Deactivation by Reduction? Chem Res Toxicol 29:270-8|
|Chang, Wei-Chen; Li, Jikun; Lee, Justin L et al. (2016) Mechanistic Investigation of a Non-Heme Iron Enzyme Catalyzed Epoxidation in (-)-4'-Methoxycyclopenin Biosynthesis. J Am Chem Soc 138:10390-3|
|Benz, Oscar S; Yuan, Quan; Amoscato, Andrew A et al. (2012) Metalloporphyrin Co(III)TMPyP ameliorates acute, sublethal cyanide toxicity in mice. Chem Res Toxicol 25:2678-86|
|Otsuka, Mai; Marks, Sarah A; Winnica, Daniel E et al. (2010) Covalent modifications of hemoglobin by nitrite anion: formation kinetics and properties of nitrihemoglobin. Chem Res Toxicol 23:1786-95|