title: Curtailing the hydroxylaminobarbituric acid-hydantoin rearrangement to favor HNO generation.
abstract: Due to its inherent reactivity, HNO must be generated in situ through the use of donor compounds. One of the primary strategies for the development of new HNO donors has been modifying hydroxylamines with good leaving groups. A recent example of this strategy is the (hydroxylamino)barbituric acid (HABA) class of HNO donors. In this case, however, an undesired intramolecular rearrangement pathway to the corresponding hydantoin derivative competes with HNO formation, particularly in the absence of chemical traps for HNO. This competitive non-HNO-producing pathway has restricted the development of the HABA class to examples with fast HNO release profiles at physiological pH and temperature (t(1/2) < 1 min). Herein, the factors that favor the rearrangement pathway have been examined and two independent strategies that protect against rearrangement to favor HNO generation have been developed. The timecourse and stoichiometry for the in vitro conversion of these compounds to HNO (trapped as a phosphine aza-ylide) and the corresponding barbituric acid (BA) byproduct have been determined by (1)H NMR spectroscopy under physiologically relevant conditions. These results confirm the successful extension of the HABA class of pure HNO donors with half-lives at pH 7.4, 37 °C ranging from 19 to 107 min.
authors.affiliation: Department of Chemistry, 3400 North Charles Street, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Guthrie
authors.forename: Saghar
authors.initials: S
authors.lastname: Nourian
authors.forename: Cyrus G
authors.initials: CG
authors.lastname: Takahashi
authors.forename: John P
authors.initials: JP
authors.lastname: Toscano
mesh_terms: D001463:Barbiturates / Q000737:chemistry*; D001669:Biochemical Phenomena; D006898:Hydroxylamines / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009589:Nitrogen Oxides / Q000737:chemistry*
chemical_list: D001463:Barbiturates; D006898:Hydroxylamines; D009589:Nitrogen Oxides; C032232:barbituric acid