N-Acetoxy

In another version of this method, the radical generated by radical exchange from the aryl telluride carbohydrate 83 and the N-acetoxy-2-thiopyridone affords, after intramolecular cyclization and desulfanylation, the polyhydroxylated and phosphorylated pseudo sugar 84 [54] (Scheme 23). 

N-Hydroxy arylamines are also converted to N-acetoxy arylamines (V), but apparently by an acetyl coenzyme A-dependent enzymatic O-esterification (7, 8). Similarly, N-sulfonyloxy arylamines (VI) are thought to arise by a PAPS-dependent enzymatic O-sulfonylation of N-hydroxy arylamines (9,10) while 0-seryl or 0-prolyl esters (VII) are formed by their corresponding aminoacyl tRNA synthetases in a ATP-dependent reaction (11,12). 

The role of N-acetoxy arylamides as metabolically formed ultimate carcinogens jji vivo also appears to be limited. Their enzymatic formation via peroxidation of N-hydroxy arylamides can be excluded since tissues containing high levels of peroxidases such as the rat mammary gland (83) and the dog urinary bladder (84) do not form acetylated carcinogen-DNA adducts in vivo (63). Their non-enzymatic formation by reaction of acetyl coenzyme A with N-hydroxy arylamides (6 ) cannot be excluded however, even if formed, their direct reaction with cellular DNA appears unlikely as treatment of cultured cells with synthetic N-acetoxy AAF (85,86) results primarily in deacetylated arylamine-DNA adducts, apparently due to rapid N-deacetylation to form the reactive N-acetoxy arylamine (V). 

From their high reactivity and nucleophilic selectivity, it seems likely that N-acetoxy arylamines readily undergo heterolytic... 

Figure 4. Reaction Mechanism for N-Acetoxy Arylamines (V). Ac, acetyl RSCH3 methionine RNH2, N2-guanine-nucleosides, -nucleotides, or -nucleic acids RCH, C8-guanine-nucleo-sides, -nucleotides, or -nucleic acids. Pathways and heterolytic cleavages a and b are discussed in the text. Dashed arrows indicate proposed pathways.

Like the N-acetoxy arylamines, a reaction mechanism for N-sulfonyloxy esters would be expected to involve formation of a nitrenium/carbenium cation-sulfate anion pair which then reacts with... 

The identification of C8-guanyl and N6-adenyl adducts of 4-aminoquinoline-l-oxide (102,103) in DNA modified by the metaboli-cally-generated 0-seryl ester and the similarity of the adduct profile with that obtained on reaction of DNA with N-acetoxy-4-araino-quinoline-l-oxide suggest an electrophilic reaction mechanism similar to that for the N-acetoxy or N-sulfonyloxy arylamines (Figures 4 and 5). However, N-seryloxy or N-prolyloxy arylamines have not been synthesized and the decomposition products of the esters generated in vitro have not yet been studied. 

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... 

N-Acetoxy arylamides carcinogenicity, 347 electrophilic reactivity, 347 properties, 347 reaction mechanism, 347-48 role as ultimate carcinogens, 347 N-Acetoxy arylamines isolation, 350... 

Aldehyde 54 and the hydroxamic acids 55 were generated together in an acid-catalysed elimination reaction (Scheme 7 pathway (ii)). A crossover experiment indicated that esters are formed in a concerted rearrangement concomitant with the likely formation of the hydroxynitrene 57 (Scheme 7 pathway (iii)) while there is no evidence to date for the formation of hydroxynitrene, joint solvolysis of equimolar quantities of /V-acetoxy-/V-butoxy-/>-chlorobenzamide 26e and N- acetoxy-/V-benzyloxybenzamide 27a afforded significant quantities of butyl p-chlorobenzo-ate (36%) and benzyl benzoate (54%) as the only esters. This is an example of a HERON reaction, which has been identified in these laboratories as a characteristic rearrangement of bisheteroatom-substituted amides.32,33,42 43 155 158 Since ester formation was shown to prevail in neutral or low acid concentrations, it could involve the conjugate anion of the hydroxamic acid (vide infra).158... 

Notably, A-(2,6-dimethylbenzyloxy)-A-acetoxybenzamide 37a and N-acetoxy-A-butoxy-3,5-dimethylbenzamide 29u (Fig. 34, black squares, Table 17, entries 39 and 40) were well modelled by QSAR (4). The difference between predicted and observed activities for 37a (—0.03) and A -acetoxy-TV-isopropoxybenzamide 25f (0.04) (Table 17, entry 4) suggests that steric effects proximate to the reactive nitrogen but on the alkoxyl side chain are less important in terms of reactivity with DNA. This is most probably a consequence of the greater flexibility in this side chain relative to the acyloxyl or amide groups. 

Poirier MC, DeCicco BT, Lieberman MW. 1975. Nonspecific inhibition of DNA repair synthesis by tumor promotors in human diploid fibroblasts damage with N-acetoxy-2-acetylaminofluorene. Cancer Res 35 1392-1397. 

Fig. 4.8. Formation of mutagenic N-hydroxyamines from arylamides. Pathway a via deacetylation and subsequent IV-hydroxylation. Pathway b via IV-hydroxylation and subsequent deacetylation. Pathway c via N-acetoxy arylamine produced by IV,0-acyltransferases. [99]. Activation of hydroxylamines and hydroxylamides by O-sulfation is not shown. In all cases, the ultimate electrophile may be a nitrenium ion.

Few split-dose experiments have been performed with chemicals. Popescu et aL (1984) observed that with split doses of carcinogen separated by 2 to 24 hours only N-acetoxy-2-fluorenylacetamide enhanced transformation of Syrian hamster embryo ceUs while doses of N-methyl-N -nitro-N-nitrosoguanidine, mitomycin C or ultraviolet light were less effective than single doses, and no effect of dose fractionation was observed with methyl methanesulfonate. 

Huang, S.L. and Lieberman, M.W. (1978). Induction of 6-thioguanine resistance in human cells treated with N-acetoxy-2-acetylaminofluorene, Mutat. Res. 57,349. 

We previously compared the properties of the reactive species involved in DNA binding by N-OH-aminofluorene, N-acetoxy-acetyl-aminofluorene and the aminofluorene products formed by a peroxidase catalyzed oxidation (28). The marked differences in reactivity suggested that different species were involved and that nitrenium ions were not responsible for the peroxidase catalyzed activation. The identity of the products formed following a peroxidase catalyzed oxidation is still not clear. Other investigators have shown the formation of nitrofluorene and azofluorene but most of the... 

ACETOXYMETHYL-N-METHYL-NITROSAMINE 1-ACETOXY-N-NITROSODIMETH-YLAMNE AMMN ANN (GERMAN) DMN-OAC ALAMN METHYL-(ACETOXYMETHYL)NITRO-SAMINE N-NITROSO-.N-(ACETOXY)METHYL-N-METHYL,Ai nNE N-NTTROSO-N-METHYL-N-ACETOXYMETHYLAMNE... 

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