N-Sulfonyloxy arylamides

Although metabolically-formed N-sulfonyloxy arylamides are strong electrophiles, bind to cellular macromolecules, and have long been considered ultimate carcinogens, their precise role in aryl-... 

Figure 2. Reaction Mechanism for N-Sulfonyloxy Arylamides (I). Ac, acetyl RSCHs, methionine RSH, glutathione or cysteine RNH2, N2-guanine- and/or N6-adenine-nucleosides, -nucleotides, or -nucleic acids RCH, C8-guanine-nucleosides, -nucleotides, or -nucleic acids, or C7-AAF.

The metabolic formation of N-sulfonyloxy-N-acetyl-2-aminofluorene (N-sulfonyloxy-AAF) and its observed electrophilic reactivity, provided the first evidence for the importance of enzymatic conjugation reactions in chemical carcinogenesis (23,24). This reaction was shown to be catalyzed by PAPS-dependent sulfotrans-ferases that are located predominantly in liver cytosol and has been subsequently demonstrated for N-hydroxy arylamide metabolites of several other carcinogens, including N-acetyl-4-aminobiphenyl (AABP), benzidine, N-acetyl-2-aminophenanthrene and phenacetin. 

Accordingly, the contribution of this metabolic activation pathway to the formation of covalently-bound adducts of arylamides with cellular proteins and nucleic acids has been the subject of numerous investigations, and has been reviewed extensively by Mulder (25). From these and more recent data (4,26,27) it is apparent, particularly in the case of N-hydroxy-AAF Tn-OH-AAF), that in vivo formation of reactive N-sulfonyloxy derivatives is primarily... 

In contrast to the reactivity of N-sulfonyloxy and N-acetoxy esters of arylamides and arylamines, the relative reactivity of protonated N-hydroxy arylamines with nucleophiles generally decreases in the order DNA > denatured DNA > rRNA = protein > tRNA nucleotides s nucleosides s methionine = GSH (2,13-17,30,36,40,127,129, 130). Furthermore, the rate of reaction with DNA was found to be not only first order with respect to N-hydroxy arylamine concentration, but also first order with respect to DNA concentration (127,129,131). These data suggested that the reaction mechanism was... 

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