Arylhydroxamic acid N,O-acyltransferase substrates. Acetyl transfer and electrophile generating activity of N-hydroxy-N-(4-alkyl-, 4-alkenyl-, and 4-cyclohexylphenyl)acetamides

• Published in: Journal of medicinal chemistry 1982-06, Vol.25 (6), p.630-638
• Main Authors: Mangold, Bonnie L. K, Hanna, Patrick E
• Format: Article
• Language: English
• Subjects: Acetamides - chemical synthesis; Acetamides - metabolism; Acetyltransferases; Acyltransferases - antagonists & inhibitors; Acyltransferases - metabolism; Animals; arylhydroxamic acid N,O-acyltransferase; Chemical Phenomena; Chemistry, Physical; Cricetinae; Dialysis; hamsters; liver; Liver - enzymology; Mesocricetus; Rats; Rats, Inbred Strains; substrate specificity; Sulfhydryl Reagents - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00348a005

Arylhydroxamic acid N,O-acyltransferase (AHAT) is an enzyme system that is capable of converting many N-arylhydroxamic acids reactive electrophilic species. As part of an investigation into the influence of the structure of the aryl group upon the ability of N-arylhydroxamic acids to serve as substrates for AHAT, a series of N-hydroxy-N-(4-alkyl-, 4-alkenyl-, and 4-cyclohexylphenyl)acetamides was prepared and evaluated in vitro with partially purified rat and hamster hepatic AHAT. The nature of the 4-substituent markedly influenced the ability of the hydroxamic acids to serve as acetyl donors in the AHAT-catalyzed transacetylation of 4-aminoazobenzene (AAB). The results of the inactivation experiments confirmed that N-hydroxy-4-acetamidobiphenyl inactivates AHAT primarily via a suicide substrate mechanism and revealed that 8 inactivates the enzyme by a process consisting primarily of a pathway in which electrophiles are released into the medium and subsequently react with nucleophiles present on AHAT.