Cyanide Scavenging by a Cobalt Schiff-Base Macrocycle: A Cost-Effective Alternative to Corrinoids.
The complex of cobalt(II) with the ligand 2,12-dimethyl-3,7,11,17-tetraazabicyclo-[11.3.1]heptadeca-1(17)2,11,13,15-pentaene (CoN4[11.3.1]) has been shown to bind two molecules of cyanide in a cooperative fashion with an association constant of 2.7 (±0.2) × 10(5). In vivo, irrespective of whether it is initially administered as the Co(II) or Co(III) cation, EPR spectroscopic measurements on blood samples show that at physiological levels of reductant (principally ascorbate) CoN4[11.3.1] becomes quantitatively reduced to the Co(II) form. However, following addition of sodium cyanide, a dicyano Co(III) species is formed, both in blood and in buffered aqueous solution at neutral pH. In keeping with other cobalt-containing cyanide-scavenging macrocycles like cobinamide and cobalt(III) meso-tetra(4-N-methylpyridyl)porphine, we found that CoN4[11.3.1] exhibits rapid oxygen turnover in the presence of the physiological reductant ascorbate. This behavior could potentially render CoN4[11.3.1] cytotoxic and/or interfere with evaluations of the antidotal capability of the complex toward cyanide through respirometric measurements, particularly since cyanide rapidly inhibits this process, adding further complexity. A sublethal mouse model was used to assess the effectiveness of CoN4[11.3.1] as a potential cyanide antidote. The administration of CoN4[11.3.1] prophylactically to sodium cyanide-intoxicated mice resulted in the time required for the surviving animals to recover from "knockdown" (unconsciousness) being significantly decreased (3 ± 2 min) compared to that of the controls (22 ± 5 min). All observations are consistent with the demonstrated antidotal activity of CoN4[11.3.1] operating through a cyanide-scavenging mechanism, which is associated with a Co(II) → Co(III) oxidation of the cation. To test for postintoxication neuromuscular sequelae, the ability of mice to remain in position on a rotating cylinder (RotaRod test) was assessed during and after recovery. While intoxicated animals given CoN4[11.3.1] did recover ∼30 min more quickly than controls given only toxicant, there were no indications of longer-term problems in either group, as determined by continuing the RotaRod testing up to 24 h after the intoxications and routine behavioral observations for a further week.
Department of Environmental and Occupational Health, Graduate School of Public Health, The University of Pittsburgh , 100 Technology Drive, Pittsburgh, Pennsylvania 15219, United States.
Elisenda
E
Lopez-Manzano
Department of Environmental and Occupational Health, Graduate School of Public Health, The University of Pittsburgh , 100 Technology Drive, Pittsburgh, Pennsylvania 15219, United States.
Andrea A
AA
Cronican
Department of Environmental and Occupational Health, Graduate School of Public Health, The University of Pittsburgh , 100 Technology Drive, Pittsburgh, Pennsylvania 15219, United States.
Kristin L
KL
Frawley
Department of Environmental and Occupational Health, Graduate School of Public Health, The University of Pittsburgh , 100 Technology Drive, Pittsburgh, Pennsylvania 15219, United States.
Jim
J
Peterson
Department of Environmental and Occupational Health, Graduate School of Public Health, The University of Pittsburgh , 100 Technology Drive, Pittsburgh, Pennsylvania 15219, United States.
Linda L
LL
Pearce
D000818:Animals; D000931:Antidotes / Q000737:chemistry / Q000191:economics / Q000494:pharmacology*; D003035:Cobalt / Q000737:chemistry / Q000191:economics / Q000494:pharmacology*; D045728:Corrinoids / Q000737:chemistry / Q000191:economics* / Q000494:pharmacology*; D003486:Cyanides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000191:economics* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D012545:Schiff Bases / Q000138:chemical synthesis / Q000737:chemistry / Q000191:economics / Q000494:pharmacology
D000931:Antidotes; D045728:Corrinoids; D003486:Cyanides; D047028:Macrocyclic Compounds; D012545:Schiff Bases; D003035:Cobalt