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Lopez-Manzano 2017 Chem Res Toxicol

From Bioblast
Publications in the MiPMap
Lopez-Manzano E, Cronican AA, Frawley KL, Peterson J, Pearce LL (2017) Cyanide scavenging by a cobalt Schiff-base macrocycle: a cost-effective alternative to corrinoids. Chem Res Toxicol 29:1011-9.

ยป PMID: 27104767

Lopez-Manzano E, Cronican AA, Frawley KL, Peterson J, Pearce LL (2017) Chem Res Toxicol

Abstract: 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 (ยฑ0.2) ร— 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 ยฑ 2 min) compared to that of the controls (22 ยฑ 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) โ†’ 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 โˆผ30 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. โ€ข Keywords: Amplex Red โ€ข Bioblast editor: Kandolf G โ€ข O2k-Network Lab: US PA Pittsburgh Peterson J

Labels: MiParea: Pharmacology;toxicology 

Preparation: Enzyme 

HRR: Oxygraph-2k, O2k-Fluorometer 

2017-05, AmR