Hydroxyurea analogues as kinetic and mechanistic probes of the nitric oxide producing reactions of hydroxyurea and oxyhemoglobin.
Derivatives of N-hydroxyurea that contain an N-hydroxy group react with oxyhemoglobin to form methemoglobin and variable amounts of nitrite/nitrate. Compounds with an unsubstituted -NHOH group produce the most nitrite/nitrate, which provides evidence for nitric oxide formation. The rate of reaction of these N-hydroxyurea derivatives with oxyhemoglobin correlates well with that compound's oxidation potential. Aromatic N-hydroxyureas react 25-80-fold faster with oxyhemoglobin than with N-hydroxyurea, suggesting other N-hydroxyurea analogues may be superior nitric oxide donors. Electron paramagnetic resonance spectroscopy shows that the formation of a low-spin methemoglobin-hydroxyurea complex is critical for iron nitrosyl hemoglobin formation. These results show that iron nitrosyl hemoglobin formation from the reaction of hydroxyureas and hemoglobin requires an unsubstituted -NHOH group and that the nitrogen atom of the non-N-hydroxy group must contain at least a single hydrogen atom. These results should guide the development of new hydroxyurea-based nitric oxide donors and sickle cell disease therapies.
Huang
Jinming
J
Departments of Chemistry and Physics, Wake Forest University, Winston-Salem, NC 27109, USA.
Zou
Zhou
Z
Kim-Shapiro
Daniel B
DB
Ballas
Samir K
SK
King
S Bruce
SB
D004563:Electrochemistry; D004578:Electron Spin Resonance Spectroscopy; D006442:Glycated Hemoglobin / Q000138:chemical synthesis; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D009566:Nitrates / Q000737:chemistry; D009569:Nitric Oxide / Q000138:chemical synthesis; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000737:chemistry; D009573:Nitrites / Q000737:chemistry; D010108:Oxyhemoglobins / Q000737:chemistry*; D013329:Structure-Activity Relationship
D006442:Glycated Hemoglobin; D006918:Hydroxyurea; D009566:Nitrates; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D009573:Nitrites; D010108:Oxyhemoglobins; C058377:hemoglobin A, glycosylated-nitric oxide complex