Banks R B, Smith T J, Hanna P E
J Med Chem. 1983 Dec;26(12):1780-4. doi: 10.1021/jm00366a026.
N-Arylhydroxamic acid N,O-acyltransferase (AHAT) is a cytosolic enzyme system that is capable of converting toxic and carcinogenic N-arylhydroxamic acids into electrophilic reactants and of catalyzing the transacetylation of arylamines. The role of the N-hydroxyl group in promoting AHAT-catalyzed transacetylation of arylamines was investigated by the synthesis and biochemical evaluation of a series of o-hydroxyaryl amides and N-arylglycolamides. Several of these compounds are metabolites of carcinogenic aryl amides in vivo. 3-Hydroxy-4-acetamidobiphenyl (8) was weakly effective as an acetyl donor when partially purified preparations of hamster or rat hepatic AHAT were used to catalyze the transacetylation of 4-aminoazobenzene. 1-Hydroxy-2-acetamidofluorene (1), 3-hydroxy-2-acetamidofluorene (2), 2-glycolamidofluorene (3), 4-glycolamidobiphenyl (9), and trans-4-glycolamidostilbene (5) were less effective acyl donors than 4-acetamidobiphenyl (7) itself. The compounds were also assayed for their abilities to participate in the AHAT-catalyzed conveydroxy-2-acetamidofluorene (1), 3-hydroxy-2-acetamidofluorene (2), 2-glycolamidofluorene (3), 4-glycolamidobiphenyl (9), and trans-4-glycolamidostilbene (5) were less effective acyl donors than 4-acetamidobiphenyl (7) itself. The compounds were also assayed for their abilities to participate in the AHAT-catalyzed conveydroxy-2-acetamidofluorene (1), 3-hydroxy-2-acetamidofluorene (2), 2-glycolamidofluorene (3), 4-glycolamidobiphenyl (9), and trans-4-glycolamidostilbene (5) were less effective acyl donors than 4-acetamidobiphenyl (7) itself. The compounds were also assayed for their abilities to participate in the AHAT-catalyzed conversion of N-arylhydroxylamines to electrophilic intermediates that form methylthio adducts upon reaction with N-acetylmethionine. None of the compounds exhibited more than 4% of the activity of the prototype compound, N-hydroxy-4-acetamidobiphenyl (10). These results indicate that the presence of an hydroxyl group on the ring position ortho to the amide group or on the alpha-position of the acyl group is not sufficient to confer significant acyltransferase activity with AHAT.
N-芳基异羟肟酸N,O-酰基转移酶（AHAT）是一种胞质酶系统，它能够将有毒和致癌的N-芳基异羟肟酸转化为亲电反应物，并催化芳胺的转乙酰化反应。通过一系列邻羟基芳基酰胺和N-芳基甘醇酰胺的合成及生化评估，研究了N-羟基在促进AHAT催化芳胺转乙酰化反应中的作用。这些化合物中的几种是致癌芳基酰胺在体内的代谢产物。当使用仓鼠或大鼠肝脏AHAT的部分纯化制剂催化4-氨基偶氮苯的转乙酰化反应时，3-羟基-4-乙酰氨基联苯（8）作为乙酰供体的效果较弱。1-羟基-2-乙酰氨基芴（1）、3-羟基-2-乙酰氨基芴（2）、2-甘醇酰胺芴（3）、4-甘醇酰胺联苯（9）和反式-4-甘醇酰胺芪（5）作为酰基供体的效果比4-乙酰氨基联苯（7）本身更差。还检测了这些化合物参与AHAT催化的N-芳基羟胺转化为亲电中间体的能力，这些亲电中间体在与N-乙酰甲硫氨酸反应时形成甲硫基加合物。这些化合物均未表现出超过原型化合物N-羟基-4-乙酰氨基联苯（10）活性的4%。这些结果表明，在酰胺基团邻位的环位置或酰基的α-位置上存在羟基不足以赋予AHAT显著的酰基转移酶活性。
