STUDIES ON THE HYDROLYSIS AND PHARMACOLOGICAL UTILITY OF "GEMINAL AMINOAMIDES"
Abstract
"Geminal aminoamides" are of interest since they have been used as amino termini in "retro-inverso" peptides, peptide protecting groups, intermediates in carboxyl-terminal peptide degradations, -amino-alkyl cation synthons and as prodrugs. The mechanism of hydrolysis of N-(1-aminoalkyl) amides has been studied. A pH rate-profile was obtained for the hydrolysis of N-(1-aminoisobutyl)-2-methoxyacetamide hydrochloride. Plateaus were observed both in the acidic and basic regions, while the rate of hydrolysis was faster in the basic region. The compounds hydrolyze to amides, aldehydes and ammonia. An iminium ion has been trapped in the basic pH region by cyanide proving it is an intermediate in hydrolysis. It has also been demonstrated that the hydrolysis of N-(1-aminoalkyl) amides is very sensitive to amide leaving group effects. Having demonstrated that an iminium ion is an intermediate product in the hydrolysis of N-(1-aminoalkyl)amides, further investigations were carried out to determine whether these compounds could act as serine protease suicide inhibitors. To date, no group has investigated whether "geminal aminoamides" can act as suicide inhibitors of acetylcholinesterase. Compounds were synthesized which were (1) "geminal aminoamides", (2) positively charged, and (3) carbamates. It has been demonstrated that (methoxycarbonyl)-amino methylamine hydrochloride is a competitive inhibitor of acetylcholinesterase. The benzyl and naphthyl derivatives proved to inhibit acetylcholinesterase over time but activity was regenerated using hydroxylamine. A preliminary study on the hydrolysis of N-((alpha)-alkoxyalkyl)amides has been carried out. N-(1-Methoxy-2-methylpropyl)acetamide. From a plot of log k 5' vs. H(,A) it was found that the hydrolysis of N-(1-methoxy-2-methylpropyl)acetamide is acid catalyzed. It has been hypothesized that N-((alpha)-alkoxyalkyl)amides might be developed as prodrugs in future research.
Degree
Ph.D.
Subject Area
Organic chemistry
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