Reactions of Substituted Pyridinium Salts with Cyanide; Formation and Metal Complexes of 2,2\u27bis (hydroxymethyl)-4,-4\u27bipyridine

The unique combination of properties of bipyridinium salts and their use in biological systems, chemical reactions, and as herbicides in agriculture have made them a discovery of major international importance. The controversy about the position of attack of the cyanide ion on the pyridine ring and the discovery of the formation of unsubstituted bipyridinium salts from the reaction of pyridinium salt with cyanide ion opened a new area of research. The current work involved a study of reactions of substituted pyridinium salts with cyanide ion. The substituted pyridinium salts were prepared by the literature methods. The 2- and 3- cyanopyridinium salts reacted with cyanide ion to form 4-cyano-1, 4-dihydropyridines. The 3, 4-dicyano-1, 4-dihydropyridines were very stable; therefore, they were isolated and characterized. An unusual product, 1-methyl-2-oxo-1, 2-dihydro-4-pyridine carbonitrile, was isolated from the reaction of 1-methyl-2-cyanopyridinium iodide with cyanide ion. The reaction of 1-benzyl-2-(acylamino) pyridinium bromide with cyanide ion did not form a 1, 4-dihydropyridine; rather, hydrogen bromide was lost when the reaction mixture was heated to a boil and 1-benzylpyridinium-2-acylimide was formed. The reaction of the 1-benzyl-2-acetylpyridinium salt, the 1-benzyl-2-bromopyridinium salt, and the 1-benzyl-2-ethylpyridinium salt with cyanide ion formed complicated products that were not characterized. The reactions of 1-benzyl-2-methylpyridinium bromide, 1-benzyl-2-(hydroxymethyl) pyridinium bromide and 1-benzyl-2, 6-dimethylpyridinium bromide with cyanide ion in water, acetone, acetone-water or 95% ethanol solutions formed dark blue or green solutions. Electron spin resonance spectroscopy showed the presence of a radical in the dark-blue or green solutions. A dark solid formed from the solutions. Oxidation of the solid with an acetone and ethanolic iodine solution or acidic ethanol solution resulted in the formation of the corresponding new, 1, 1\u27-dibenzyl-2, 2\u27-bis(hydroxymethyl)-4-4\u27-bipyridinium dibromide 75, and the known 1, 1\u27-dibenzyl-2, 2\u27-dimethyl-4, 4\u27-bipyridinium dibromide, and 1, 1\u27-dibenzyl-2, 2\u27, 6, 6\u27-tetramethyl-4, 4\u27-bipyridinium dibromide dimers. The new dimer 75 was reduced in aqueous solution at potential (E°) of about -0.34V vs NHE. It was also debenzylated with triphenylphosphine in refluxing DMF to give 2, 2\u27-bis(hydroxymethyl)-4, 4\u27-bipyridine 89. 1, 1\u27-Dibenzyl-2, 2\u27-dimethyl-4, 4\u27-bipyridinium dibromide was also debenzylated to give 2, 2\u27-dimethyl-4, 4\u27 bipyridine, which was acidified with hydrogen chloride gas, and the salt 2\u27, 2\u27-dimethyl-4, 4\u27-bipyridyl dihydrochloride was formed. These were the first report on debenzylation of bipyridinium dimers. The reaction of 89 with cobalt thiocyanate formed a new 2, 2\u27-bis(hydroxymethyl)-4, 4\u27-bipyridine cobalt thiocyanate octahedral complex. The reaction of 2-(hydroxymethyl)pyridine and 2-(2-hydroxyethyl) pyridine with cobalt thiocyanate gave the corresponding octahedral complexes

Molecular Defects of Vitamin B6 Metabolism Associated with Neonatal Epileptic Encephalopathy

Neonatal epileptic encephalopathy (NEE) is a seizure disorder that occurs within hours from birth and arises from central nervous system (CNS) dysfunctions of various origins, including metabolic or inflammatory conditions, abnormalities of brain structure and cerebrovascular diseases. In some rare circumstances, NEE is refractory to conventional antiepileptic drugs (AEDs) but responds very well to treatment with vitamin B6 in the form of either pyridoxine (PN) or pyridoxal 5’-phosphate (PLP). Vitamin B6-dependent NEE derives either from a deficiency of PLP, from inborn errors in enzymes, such as pyridoxine 5’-phosphate oxidase (PNPOx) and pyridoxal kinase (PL kinase) involved in the PLP salvage pathway or from inherited mutations of enzymes, such as -aminoadipic semialdehyde dehydrogenase (also known as antiquitin) involved in other metabolic pathways, which lead to the accumulation of intermediates that react with PLP, reducing its availability. Clinical phenotypes observed in vitamin B6-dependent NEE patients may include fetal distress, hypoglycemia, acidosis, anemia, and asphyxia. The health state of untreated patients may undergo progressive deterioration, which can lead to death within weeks. Surviving children are usually mentally retarded and are dependent on vitamin B6 to control the disease. Several known cases of B-dependent NEE, however do not or only mildly manifest some of the above clinical features, and are characterized by mild to moderate developmental delay. This chapter will review the molecular mechanism of how in-born errors in PNPOx or antiquitin affect PLP levels in the cell and lead to NEE. We will also review important clinical and general features associated with PLP dependent NEE, and provide some directions for clinicians to diagnose and treat or manage the diseas