Rearrangement of 4-amino-3-halo-pyridines by nucleophilic aromatic substitution.

The reaction of 3-halo-4-aminopyridines with acyl chlorides and triethylamine is described. The pyridin-4-yl α-substituted acetamide products were obtained in moderate to high yields. The presented rearrangement reaction, in which the presumed N-acylated intermediate reacts intramolecularly via nucleophilic aromatic substitution, results in a formal two-carbon insertion.

Passive Membrane Permeability of Macrocycles Can Be Controlled by Exocyclic Amide Bonds.

We have developed a strategy for synthesizing passively permeable peptidomimetic macrocycles. The cyclization chemistry centers on using aziridine aldehydes in a multicomponent reaction with peptides and isocyanides. The linker region in the resulting product contains an exocyclic amide positioned α to the peptide backbone, an arrangement that is not found among natural amino acids. This amide provides structural rigidity within the cyclic peptidomimetic and promotes the creation of a stabilizing intramolecular hydrogen bonding network. This exocyclic control element also contributes to the increased membrane permeability exhibited by multicomponent-derived macrocycles with respect to their homodetic counterparts. The exocyclic control element is employed along with a strategic placement of N-methyl and d-amino acids to produce passively permeable peptides, which contain multiple polar residues. This strategy should be applicable in the pursuit of synthesizing therapeutically relevant macrocycles.

Dopamine-ß-Hydroxylase Activity and Levels of Its Cofactors and Other Biochemical Parameters in the Serum of Arsenicosis Patients of Bangladesh.

Dopamine-ß-hydroxylase (DBH) is a neurotransmitter (catecholamine)-mediating enzyme, which catalyzes the formation of norepinephrine from dopamine. The levels of DBH activity, its coenzyme (ascorbic acid) and cofactor (Cu(++)) and other biochemical parameters were measured in the serum of 32 arsenicosis patients of Bangladesh at three different age groups, namely, group 1 (10-18 years, 9 patients), group 2 (19-40 years, 14 patients) and group 3 (41-70 years, 9 patients) of the locality of Stadium Para of Meherpur district of Bangladesh. The values were compared with the same number of age-matched normal healthy individuals of the respective group. DBH activity was markedly decreased in the patients of group 1 as compared to that of the normal healthy people. The activities of DBH were decreased to lesser extents for the other two age groups. The total protein contents in the serum of arsenicosis patients were also significantly low as compared to that in the age-matched control groups. The levels of ascorbic acid and copper were found to be decreased in the serum of arsenicosis patients. The serum glucose levels were elevated in arsenicosis patients, as compared to that of the respective healthy controls. Other parameters, such as zinc and vitamin A levels were also decreased in the serum of arsenicosis patients. It was evident from the results of drinking of the arsenic contaminated water of shallow tube wells that the levels of DBH activity decreased significantly as compared to the control healthy persons. The levels of proteins, ascorbic acid, copper, zinc and vitamin A were decreased in the serum of people drinking the arsenic contaminated tube wells water as compared to that in the control healthy people with the exception that the levels of glucose were elevated in the serum of these patients. The pathophysiological significance of the results could be correlated with the decreased in proteins and that in DBH activities as DBH deficiency is characterized by lack of sympathetic noradrenergic function.The general physiologic findings of autonomic function indicate that complete DBH deficiency include minimal or absent plasma norepinephrine and epinephrine.