N-Hydroxyurea and Acyl Nitroso Compounds as Nitroxyl (HNO) and Nitric Oxide (NO) Donors

Abstract

Hydroxyurea has emerged as a new therapy for sickle cell disease but a complete mechanistic description of its beneficial actions does not exist. Patients taking hydroxyurea show evidence for the in vivo conversion of hydroxyurea to nitric oxide (NO), which also has drawn interest as a sickle cell disease treatment. While the chemical oxidation of hydroxyurea produces NO or NO-related products, NO formation from the reactions of hydroxyurea and hemoglobin do not occur fast enough to account for the observed increases in patients taking hydroxyurea. Both horseradish peroxidase and catalase catalyze the rapid formation of nitric oxide and nitroxyl (HNO) from hydroxyurea. In these reactions, hydroxyurea is converted to an acyl nitroso species that hydrolyzes to form HNO. The ferric heme protein then oxidizes HNO to NO that combines with the heme iron to form a ferrous-NO complex that may act as an NO donor. In general, acyl nitroso compounds, regardless of the method of their preparation, hydrolyze to form HNO and the corresponding carboxylic acid derivative. Similarly, the incubation of blood and hydroxyurea with urease rapidly form NO-related species suggesting the initial urease-mediated hydrolysis of hydroxyurea to hydroxylamine, which then reacts quickly with hemoglobin to form these products. These studies present two NO releasing mechanisms from hydroxyurea that are kinetically competent with clinical observations.

Generation of nitroxyl by heme protein-mediated peroxidation of hydroxylamine but not N-hydroxy-L-arginine

“…When activated by H 2 O 2 , hemes peroxidatively modify a wide variety of substrates. Of importance here is that reduced nitrogen compounds, such as the hydroxylamine-derivative hydroxyurea, can be peroxidatively converted to HNO [48]. Such pharmacological production of HNO raises the issue of whether endogenous substrates can similarly function as biosynthetic precursors to HNO [49][50][51].…”

“…9) or that production of NO leads to formation of an intermediate capable of oxidizing NO. Interestingly, catalase oxidizes both cyanamide [16] and hydroxyurea [48] to HNO. Further studies examining the effects of heme axial ligation on HNO formation are required.…”

The Specificity of Nitroxyl Chemistry Is Unique Among Nitrogen Oxides in Biological Systems

“…1 (84,89) The two most commonly used donors of HNO are Angeli's salt (sodium trioxodinitrate, Na 2 N 2 O 3 ) and derivatives of sulfohydroxamic acid, particularly Piloty's acid (benzenesulfohydroxamic acid, C 6 H 5 SO 2 NHOH). Several clinically used compounds such as cyanamide and hydroxyurea can also be bioactivated to HNO [for reviews on HNO donors, see (70,79,80,110)]. …”

Synthesis, antibacterial and cytotoxic activity evaluation of hydroxyurea derivatives

“…In this paper, the synthesis of new hydroxyurea cyclic and acyclic derivatives [1-(N-metoxycarbamoyl)benzotriazole (3), 1-(N-ethoxycarbamoyl)benzotriazole (4), N-benzyloxybiuret (6), 4-{[(benzyloxy)carbamoyl]amino}benzoic acid (7), 4-{[(hydroxy)carbamoyl]amino}benzoic acid (13) and N,N',N''-trihydroxybiuret (15)] and new synthetic routes for these groups of compounds [1,1'-carbonylbisbenzotriazole (1), N-benzyloxycarbamoyl)benzotriazole (2), N,N'-bisbenzyloxyurea (9), N-hydroxybiuret (12) and N-hydroxurea (14)] are disclosed. Metabolic activity test showed the cytotoxic potential of twelve compounds (2-4, 7, 9 and 11-17).…”