Azide is a mitochondrial poison, easily obtained, with the potential for use by terrorists. At neutral pH azide exists largely in its anionic form, N3?, is tasteless, odorless and is not easily lost to the environment. It is, therefore, a perfect poison for delivery by ingestion and has been used as such in the United States and Japan. In addition, treatment of sodium azide with acid will generate HN3 gas, which has the potential for causing mass casualties through inhalation. There presently seems to be no approved therapeutic protocol for treating azide-poisoning victims. Similar to cyanide, the azide anion binds to cytochrome c oxidase, a critically important mitochondrial protein, inhibiting electron transport. As the nitrite/thiosulfate combination is an approved antidote for cyanide, others have suggested using this combination for azide poisoning, but we have recently found that nitrite is ineffective as an antidote for azide poisoning and may, in fact, be detrimental. Building on our recent experience with a cobalt(III)- containing water-soluble porphyrin that we have demonstrated to be an effective cyanide antidote in mice [Benz et al (2012) Chem Res Tox, 25, 2678-86; Ibid (2016)] 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 will be good candidate antidotes for azide poisoning. The straightforward syntheses of many inexpensive and stable complexes of cobalt(III) having this necessary surrounding ligand geometry are known and many more are accessible via derivatization of the compounds already in the existing literature. We expect complexes, in which the cobalt(III) ion is retained by polydentate ligands, will be non- toxic at the levels required to be efficacious in treating azide intoxication.
Aim 1. Demonstrate that some easily prepared cobalt(II/III) complexes are candidate azide (N3?) antidotes by virtue of their azide binding characteristics in aqueous buffer.
Aim 2. Demonstrate in mice the efficacy of the most promising candidate azide antidotes, their inherent safety, and primary route(s) of excretion.
The poisoning of water with salts of azide is a fairly low-tech potential terrorist weapon that could be devastating to communities. Azide salts are stockpiled throughout the US and are easily available on-line, rendering the possibility of such attacks especially worrisome. There is currently no known treatment for azide poisoning. In fact one of the treatments currently approved for a similar poison, cyanide, would be deadly instead of ameliorating. Cognizant of the long-term desirability of easy mass production and stockpiling, we propose to develop a new class of azide-decorporating agent that can be synthesized in no more than two steps and requiring only inexpensive starting materials.
