Diethylcarbamoylating/Nitroxylating Agents as Dual Action Inhibitors of Aldehyde Dehydrogenase:  A Disulfiram−Cyanamide Merger

Benzenesulfohydroxamic acid (Piloty's acid) was functionalized on the hydroxyl group with the N,N-diethylcarbamoyl group, and the hydroxylamine nitrogen was substituted with acetyl (1a), pivaloyl (1b), benzoyl (1c), and ethoxycarbonyl (1d) groups. Only compound 1d inhibited yeast aldehyde dehyd...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1999-10, Vol.42 (20), p.4016-4020
Main Authors: Conway, Terry T, DeMaster, Eugene G, Goon, David J. W, Shirota, Frances N, Nagasawa, Herbert T
Format: Article
Language:English
Subjects:
Acetaldehyde - blood
Alcohol Deterrents - chemical synthesis
Alcohol Deterrents - chemistry
Alcohol Deterrents - pharmacology
Alcoholism and acute alcohol poisoning
Aldehyde Dehydrogenase - antagonists & inhibitors
Animals
Biological and medical sciences
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Ethanol - pharmacology
Hydroxamic Acids - chemical synthesis
Hydroxamic Acids - chemistry
Hydroxamic Acids - pharmacology
Male
Medical sciences
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
Toxicology
Yeasts - enzymology
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Summary:Benzenesulfohydroxamic acid (Piloty's acid) was functionalized on the hydroxyl group with the N,N-diethylcarbamoyl group, and the hydroxylamine nitrogen was substituted with acetyl (1a), pivaloyl (1b), benzoyl (1c), and ethoxycarbonyl (1d) groups. Only compound 1d inhibited yeast aldehyde dehydrogenase (AlDH) in vitro (IC50 169 μM). When administered to rats, 1d significantly raised blood acetaldehyde levels following ethanol challenge, thus serving as a diethylcarbamoylating/nitroxylating, dual action inhibitor of AlDH in vivo. A more potent dual action agent was N-(N,N-diethylcarbamoyl)-O-methylbenzenesulfohydroxamic acid (5c), which was postulated to release diethylcarbamoylnitroxyl (9), a highly potent diethylcarbamoylating/nitroxylating agent, following metabolic O-demethylation in vivo. The dual action inhibition of AlDH exhibited by 1d, and especially 9, constitutes a merger of the mechanism of action of the alcohol deterrent agents, disulfiram and cyanamide.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm990235p