N-Arylhydroxamic acids

Thionyl chloride reacts with N-arylhydroxamic acids to form the corresponding amides via ortho-halogenation (equation 30). ... 

Gupta VK, Tandon SG. 1973. N-Arylhydroxamic acids as reagents for vanadium (V). Spectrophotometric determination of vanadium (V) with N-M-Tolyl-p-methoxybenzohydroxamic acid. Anal Chim Acta 66 39- 48. 

Tiwari, V. and Pande, R. (2006) Molecular descriptors of N-arylhydroxamic acids a tool in drug design. Chem. Biol Drug Des., 68, 225-228. 

Sakamoto, Y, T. Yoshioka and T. Uematsu. 1989. N-Arylhydroxamic acids reaction of nitroso aromatics with a-oxo acids. J. Org. Chem. 54 4449-4453. 

Novak, M., Kahley, M. J., Lin, J., Kennedy, S. A., and James, T. G., Involvement of free nitrenium ions, ion pairs, and preassociation trapping in the reactions of ester derivatives of N-arylhydrox-ylamines and N-arylhydroxamic acids in aqueous solutions, /. Org. Chem., 60, 8294, 1995. 

Despite the typical use of the 1,5-dienic system in the hetero-Cope rearrangement the participation of triple bonds, C=N and C=C, in the [3,3]-sigmatropic rearrangement was also reported. Synthesis of A-substituted benzimidazolinones 175 by a hetero-Cope rearrangement of the adduct 174 formed by reaction of A-arylhydroxamic acids 172 with cyanogen bromide 173 in the presence of triethylamine and at low temperatures was reported by Almeida, Lobo and Prabhakar (equation 51). 

Figure 7.1 Some of the possible routes of metabolic activation of AAF. Abbreviations-. AAF, acetylamino-fluorene N-OH-AF, /V-hydroxyaminofluorene N-OH-AAF, /V-hydroxyacetylaminofIuorene A/-acetoxy AF, N-acetoxyaminofluorene N-(dG-8yl)-AF, AAdeoxyguanosinyl-aminof I uo rene N-(dG-8yl)-AAF, A/-deoxyguanosinyl-acety-laminofluorene P-450, cytochrome(s) P-450 DA, deacetylase NAT, A/-acetyltransferase AHAT, N, O-arylhydroxamic acid acyltransferase.

N,0-Acyltransferase. The /V-acyl transferase enzyme is believed to be involved in the carcinogenicity of arylamines. These compounds are first V-oxidized, and then, in species capable of their A-acetylation, acetylated to arylhydroxamic acids. The effect of N, O-transacetylation is shown in Figure 7.22. The A/-acyl group of the hydroxamic acid is first removed and is then transferred, either to an amine to yield a stable amide or to the oxygen of the hydroxylamine to yield a reactive N-acyloxyarylaminc. These compounds are highly reactive in the formation of adducts with both proteins and nucleic acids, and N, O -acy I Iransfcrasc, added to the medium in the Ames test, increases the mutagenicity of compounds such as A-hydroxy-2-acetylaminofluorine. 

Figure 7.22 N-, O-Acyltransferase reactions of arylhydroxamic acid. Ar = aryl group.

MCRs Involving Amidation of Carbonyls with Nitroso Compounds NHC-catalyzed direct amidation of carbonyls with nitroso compounds is a powerful method for the synthesis of A-arylhydroxamic acids 50 and their derivatives [39] (Scheme 5.33). The strategy exploits the reactivity of nitroso compounds as electrophiles, which allows reaction with intermediate 134, forming the corresponding C—N bonds. 

An unusual enzymatic action has been described in which arylhydroxamic acids were converted to arylhydroxylamine-O-ester (Fig. 16). This is thermodynamically unfavorable in most cases and is probably achieved as the result of the further rapid reactions of the latter which serve to displace the enzyme-mediated equilibrium between the arylhydroxamic acid compound and arylhydroxylamine-O-ester. The enzyme that catalyzes this reaction is called arylhydroxamic acid-N,0-acyl transferase (50, 51) and is either closely associated with or identical to the enzyme which catalyzes 0-acetylation of arylhydroxylamine compounds (64). In turn, it appears that the enzyme which catalyzes these two reactions may be the same as N-acetyltransferase, which is a rather non-specific enzyme that catalyzes reversible N-acetylations of arylamine and arylhydroxylamine compounds. These functions are depicted in Figure 16 for arylhydroxylamine metabolism, and their contributions to the bioactivation of arylhydroxylamine and aryl hydroxamic acid compounds are a major research area in arylamine toxicity (51). 

Figure 16. Schematic presentation of reversible enzymatic acetylation reactions of arylamines (Ar-NH2) and arylhydroxylamines (Ar-NHOH) and the N,0-acyltransfer reaction of arylhydroxamic acids (ArNOHCOCH3).

Enzymatic conversion of arylhydroxylamine and arylhydroxamic acid compounds to highly reactive 0-esters is often accompanied by progressive inactivation of the responsible enzyme (66). This suicide inhibition has been extensively investigated, particularly in the case of N,0-acyltransferase (6) and more recently for sulfotransferase (70,85). The probable cause is covalent binding of some of the activated metabolite to the enzyme. Such adduction is to be expected when a highly reactive metabolite is produced in close proximity to a biomolecule that possesses nucleophilic groups. The responsible enzyme often becomes the first biomolecule to be damaged by the electrophilic species that it produced. 

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