Analogues of N-hydroxy-4-acetylaminobiphenyl as substrates and inactivators of hamster hepatic acetyltransferases.
1. A series of analogues of N-hydroxy-4-acetylaminobiphenyl (1, N-OH-AAB) has been synthesized and evaluated in vitro as substrates and inactivators of hamster hepatic N,N-acetyltransferase (N,N-AT) activity. The analogues of 1 are N-arylhydroxamic acids in which an atom or small functional group has been incorporated between the phenyl rings of 1. 2. The structural and molecular properties of the atoms between the two phenyl rings had little influence on the ability of the compounds to serve as acetyl donors in the N-arylhydroxamic acid-dependent transacetylation of 4-aminoazobenzene (AAB) catalysed by N,N-AT. An exception was the SO2 analogue (6) which was inactive. 3. All of the compounds except 6 were mechanism-based inactivators (suicide inhibitors) of hamster hepatic N,N-AT. The inhibition of N,N-AT by the hydroxamic acids was irreversible. The properties of the atom or functional group between the phenyl rings had a substantial influence on the relative effectiveness of the compounds as inactivators of N,N-AT. trans-N-Hydroxy-4-acetylaminostilbene (N-OH-AAS, 7) was the most potent and effective mechanism-based inactivator among the compounds studied. The ketone analogue (2) was the least effective among the compounds that exhibited inactivating activity. 4. The presence of the nucleophile cysteine in the incubation mixtures reduced the extent of inactivation of N,N-AT by 1 and by the ether (4) analogue but had little effect on the inactivation caused by 7. The inactivation of N,N-AT by N-OH-AAS (7) does not appear to involve electrophiles that are released from the active site and subsequently become covalently bound to the enzyme.
Hanna
P E
PE
Department of Medicinal Chemistry, University of Minnesota, Minneapolis 55455.
el-Ghandour
A M
AM
McCormack
M E
ME
D000107:Acetylation; D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000611:Aminobiphenyl Compounds / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D006224:Cricetinae; D003545:Cysteine; D006877:Hydroxamic Acids / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D008647:Mesocricetus; D015394:Molecular Structure; D013267:Stilbenes / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010128:p-Aminoazobenzene / Q000378:metabolism
D000611:Aminobiphenyl Compounds; D006877:Hydroxamic Acids; D013267:Stilbenes; C001367:N-hydroxy-4-acetylaminostilbene; C001365:N-hydroxy-4-acetylaminobiphenyl; D010128:p-Aminoazobenzene; D000123:Acetyltransferases; D003545:Cysteine