RESUMO
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) â 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 â¼30 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.
Assuntos
Antídotos/farmacologia , Cobalto/farmacologia , Corrinoides/economia , Corrinoides/farmacologia , Cianetos/antagonistas & inibidores , Compostos Macrocíclicos/economia , Compostos Macrocíclicos/farmacologia , Animais , Antídotos/química , Antídotos/economia , Cobalto/química , Cobalto/economia , Corrinoides/química , Cianetos/química , Cianetos/toxicidade , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Masculino , Camundongos , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/economia , Bases de Schiff/farmacologiaRESUMO
Cassava (Manihot esculenta Crantz) is a staple food for more than 500 million people, especially in Africa and South America. However, its consumption bears risks as it contains cyanogenic glycosides that convert enzymatically to toxic cyanide during cell damage. To avoid serious health problems by unintentional cyanide intake, this dangerous product of decomposition must be removed before consumption. For monitoring such food processing procedures and for controlling the quality and safety of cassava products on the market, a convenient and reliable analytical method for routine applications without laboratory equipment is required. This Perspective summarizes the authors' work on corrin-based chemosensors for the ('naked-eye') detection of endogenous cyanide in cassava samples. Considering selectivity, sensitivity, handling and speed of detection, these systems are superior to currently applied methods. Based on these properties, the development of a test kit for application by rural farmers in remote locations is proposed.