N-Hydroxyamides

Synthesis, reactions, and metal-chelating properties of functionalized heterocycles possessing N-hydroxyamide moiety 97YGK524. 

On reaction with hydroxylamine in the presence of appropriate bases, such derivatives of D-glucofuranurono-6,3-lactones as 25, 26, and 33 form114 N-hydroxyamides. On the other hand, when treated with hydroxylamine without base catalysis, compound 4 yields115 aWeJjt/do-D-glucurono-6,3-lactone oxime. 

Free N-hydroxyamino acids (1) or (2) have never been isolated from living organisms, probably because of their instability. As already mentioned, N-hydroxyamino acid residues occur only as fragments of many natural products containing the N-hydroxyamide bond. The isolation of free N -hydroxy-L-arginine from the fermentation medium of Bacillus cereus (6, 7) may be considered as an exception however, this compound contains an N-hydroxyguanidine rather than an N-hydroxyamine group. 

N-Hydroxyamino acids, similar in action to N-hydroxyurea, some N-hydroxyamides and some aromatic hydroxy acids, are inhibitors of ribonucleotide reductases 112), a unique group of metalloenzymes, essential for cell proliferation. Inhibition of substrate reduction in vitro (l5o = 2.3-10 ) is accompanied by decay of the tyrosyl radical but not the iron atom from the E. coli subunit B2 of this enzyme. Inhibitors of the above type donate an electron to the enzyme s free radical, producing an inactive protein-enzyme with a still intact binuclear iron complex and a new more stable free radical of the nitroxide type (52)... 

The biogenesis of the N-hydroxyamide bond is an interesting problem 115). That it may involve oxidation of the a- or co-amine group of an amino acid to a hydroxylamine derivative (Scheme 14, path a) was observed in the biosynthesis of ferrichrome (5) 116), hadacidin (13) (25, 117) and aerobactin (8) 118). 

The synthesis of mycelianamide (Scheme 62) (14) 210 a naturally occurring benzylidene-2,5-dioxopiperazine residue, with protection of the olefmic bond as well as the N-hydroxyamide function, is an interesting solution. 

Figure 7.54 Acetaminophen undergoes N-oxidation to form an N-hydroxyamide. When a base removes a proton from the phenol electrons flow into the ring and displace the OH group to form an electrophile known as an iminoquinone. This is known to be toxic to the liver when formed in large quantities, such as after an overdose of acetaminophen. Normally, however, there is sufficient GSH present to detoxify this metabolite when the drug is taken in the prescribed amount. In this case GSH adds to the electrophile, aided by GST, to give an intermediate that tautomerizes to a phenol, but with GSH covalently bound to the 2-position.

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