The Nitric Oxide Producing Reactions of Hydroxyurea

King, S. Bruce

doi:10.2174/0929867033368213

Cited by 87 publications

(84 citation statements)

References 89 publications

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“…For instance, HNO is the active metabolite of the alcohol sensitizing drug cyanamide (NH 2 CN) [16], which is used for pharmacotherapy of alcohol abuse. Additionally, hydroxyurea, which is a chemotherapeutic used to reduce the complications of sickle cell disease, was found to be oxidatively degraded to HNO [17,18]. Although endogenous production of HNO has yet to be demonstrated in vivo, numerous in vitro assays have indicated the existence of several potential biosynthetic mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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

Donzelli

Espey

Flores-Santana

et al. 2008

Free Radical Biology and Medicine

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The chemical reactivity, toxicology and pharmacological responses to nitroxyl (HNO) are often distinctly different from those of nitric oxide (NO). The discovery that HNO donors may have pharmacological utility for treatment of cardiovascular disorders such as heart failure and ischemia reperfusion has led to increased speculation of potential endogenous pathways for HNO biosynthesis. Here, the ability of heme proteins to utilize H 2 O 2 to oxidize hydroxylamine (NH 2 OH) or N-hydroxy-L-arginine (NOHA) to HNO was examined. Formation of HNO was evaluated with a recently developed selective assay in which the reaction products in the presence of reduced glutathione (GSH) were quantified by HPLC. Release of HNO from the heme pocket was indicated by formation of sulfinamide (GS(O)NH 2 ), while the yields of nitrite and nitrate signified the degree of intramolecular recombination of HNO with the heme. Formation of GS(O)NH 2 was observed upon oxidation of NH 2 OH, whereas NOHA, the primary intermediate in oxidation of L-arginine by NO synthase, was apparently resistant to oxidation by the heme proteins utilized. In the presence of NH 2 OH, the highest yields of GS(O)NH 2 were observed with proteins in which the heme was coordinated to a histidine (horseradish peroxidase, lactoperoxidase, myeloperoxidase, myoglobin and hemoglobin) in contrast to a tyrosine (catalase) or cysteine (cytochrome P450). That peroxidation of NH 2 OH by horseradish peroxidase produced free HNO, which was able to affect intracellular targets, was verified by conversion of 4,5-diaminofluorescein to the corresponding fluorophore within intact cells.

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Section: Introductionmentioning

confidence: 99%

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

Donzelli

Espey

Flores-Santana

et al. 2008

Free Radical Biology and Medicine

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“…8 Hydroxyurea is completely absorbed and elimination is through both renal and nonrenal mechanisms. 9 The metabolism of hydroxyurea to NO most likely occurs in the liver. 3 Chemical oxidation of hydroxyurea with a variety of oxidants, including copper(II) ions, produces NO.…”

Section: Introductionmentioning

confidence: 99%

“…3 Chemical oxidation of hydroxyurea with a variety of oxidants, including copper(II) ions, produces NO. 9,10 Hydroxyurea-treated vascular endothelial cells showed significant morphologic changes such as an increase in apparent cell size, accompanied by an increase in cell Na and K contents. 11 During hydroxyurea treatment, cells accumulate in the late G1 to early S phase of the cell cycle.…”

Section: Introductionmentioning

confidence: 99%

Hydroxyurea induces the eNOS-cGMP pathway in endothelial cells

Čokić¹,

Beleslin-Čokić²,

Tomić³

et al. 2006

Blood

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Hydroxyurea is a cell-cycle-specific drug that has been used to treat myeloproliferative diseases and sickle cell anemia. We have recently shown that hydroxyurea, like nitric oxide (NO)-donor compounds, increased cGMP levels in human erythroid cells. We show now that hydroxyurea increases endothelial-cell production of NO; this induction of NO in human umbilical vein endothelial cells (HUVECs) and human bone marrow endothelial cell line (TrHBMEC) is blocked by competitive inhibitors of NO synthase (NOS), such as N G -nitro-L-arginine-methyl ester (L-NAME) and N G -nitro-L-arginine. It is dependent on cAMP-dependent protein kinase (PKA) and protein kinase B (PKB/Akt) activity. We found that hydroxyurea dose-and time-dependently induced rapid and transient phosphorylation of eNOS at Ser1177 in a PKA-dependent manner; inhibitors of PKB/Akt could partially abrogate this effect. In addition, hydroxyurea induced cAMP and cGMP levels in a dose-dependent manner, as well as levels of intracellular calcium in HUVECs. These studies established an additional mechanism by which rapid and sustained effects of hydroxyurea may affect cellular NO levels and perhaps enhance the effect of NO in myeloproliferative diseases. IntroductionHydroxyurea is a cytostatic agent (S-phase inhibitor) that has been used to treat erythrocytosis and thrombocytosis in polycythemia vera and other myeloproliferative diseases. 1 More recently, hydroxyurea demonstrated therapeutic benefit for sickle cell anemia by increasing fetal hemoglobin (HbF). 2 In addition to the known inhibition of ribonucleotide reductase, hydroxyurea can be oxidized by heme groups to produce nitric oxide (NO) in vivo (in rats) and in humans. 3,4 Hydroxyurea reacts with oxyHb and deoxyHb to form metHb, which then reacts with another hydroxyurea to form iron nitrosyl hemoglobin (HbNO). 5 The formation of HbNO involves the specific transfer of NO from the -NHOH group of hydroxyurea by a series of intermediate reactions. 3 Additionally, in vivo production of NO may result from the hydrolysis of hydroxyurea to hydroxylamine, followed by the rapid reactions of hydroxylamine with Hb. 6 It has been reported that hydroxyurea administration significantly increased NO x (NO metabolites nitrite and nitrate) and cGMP levels in plasma of sickle cell patients. 7 We have recently shown that hydroxyurea, like NO-donor compounds, increased cGMP levels contributing to gamma-globin gene expression in human erythroid cells. 8 Hydroxyurea is completely absorbed and elimination is through both renal and nonrenal mechanisms. 9 The metabolism of hydroxyurea to NO most likely occurs in the liver. 3 Chemical oxidation of hydroxyurea with a variety of oxidants, including copper(II) ions, produces NO. 9,10 Hydroxyurea-treated vascular endothelial cells showed significant morphologic changes such as an increase in apparent cell size, accompanied by an increase in cell Na and K contents. 11 During hydroxyurea treatment, cells accumulate in the late G1 to early S phase of the cell cycle. 12 Also, the level...

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“…5) HU causes an immediate inhibition of DNA synthesis by acting on the R 2 subunit of the ribonucleotide reductase. [6][7][8] Therapeutic application of HU has several disadvantages such as short half-life (1.9-3.9 h) in patients due to its small molecular size (MWϭ76.06) and extremely polar nature (Clog P o/w ϭ Ϫ1.80), the necessity of using a high dosage (80 mg/kg every third day or 20-30 mg/kg daily), and the rapid development of resistance. 1,[9][10][11] In this study, structure modification of HU based on increasing its hydrophobic nature and molecular size has been adopted to obtain a more potent compound.…”

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confidence: 99%

Synthesis, Antitumor Evaluation and Crystal Structure of Hydroxyurea Derivatives

Mai

Xia

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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Hydroxyurea (HU) has been used in cancer chemotherapy for many years. It has been of manifold pharmacological interest, so it has been used for the treatment of melanoma, chronic myelocytic leukemia, and recurrent, metastatic, or inoperable ovarian cancer. HU is also used in therapy of squamous cell carcinomas in the head and neck and relapsed metastasis ovarian cancer, 1) and people have found that it has certain effect on sickle cell anemia, 2) beta-thalassemia, 3) and psoriasis.4) It is also reported that HU has been used for the treatment of AIDS in combination with didanosine, showing no viral rebound after one year treatment.5) HU causes an immediate inhibition of DNA synthesis by acting on the R 2 subunit of the ribonucleotide reductase.6-8) Therapeutic application of HU has several disadvantages such as short half-life (1.9-3.9 h) in patients due to its small molecular size (MWϭ76.06) and extremely polar nature (Clog P o/w ϭ Ϫ1.80), the necessity of using a high dosage (80 mg/kg every third day or 20-30 mg/kg daily), and the rapid development of resistance. 1,[9][10][11] In this study, structure modification of HU based on increasing its hydrophobic nature and molecular size has been adopted to obtain a more potent compound. A series of monosubstituents and disubstituents of HU with different benzyls were synthesized and their structures were elucidated using spectrometry along with X-ray crystal structures analysis for representative compounds. The antitumor activity tests in vitro for human tongue cancer cell line and murine leukemia cell line were evaluated. Results and DiscussionSynthesis The target compounds were prepared using the reaction sequence in Chart 1. The compounds 2a-f were synthesized in good yield by condensation of HU with various benzyls (1a-f) in the presence of potassium hydroxide under reflux. The condensation of 2a-f with HU afforded compounds 3a-f. The chemical structures of the synthesized compounds (2a-f and 3a-f) were confirmed by spectroscopic methods, and exact stereostructures of compounds 2a and 3f have been determined by X-ray crystal structure analysis.X-Ray Crystal Structure Analysis The crystallographic data of 2a are summarized in Table 1. The selected bond lengths, angles and torsion angles are given in Table 2. ORTEP drawings of the compounds 2a and 3f 12) are illustrated in Fig. 1. Crystallographic data and the structure analysis of compound 3f have been outlined in the previous paper.12) Conformations of the C8ϭO2 double bond and N1-O1 bond in 2a are the opposite of each other, similar to that observed in 3f (C1ϭO2 double bond and N1-O1 bond), N-hydroxyurea [13][14][15][16][17] and other hydroxyurea derivates.18) The length of the carbonyl bond (C8ϭO2) in 2a is in the normal range of 1.19-1.23 Å, similar to that observed in 3f, 12) but obviously shorter than N-hydroxyurea, 1-hydroxy-1-methylurea and 1-hydroxy-3-methylurea (Ͼ1.25 Å). This may be related to the hydroxyl etherification. The average distance between the carbon atom and the coordination nitrogen atom i...

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The Nitric Oxide Producing Reactions of Hydroxyurea

Cited by 87 publications

References 89 publications

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

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

Hydroxyurea induces the eNOS-cGMP pathway in endothelial cells

Synthesis, Antitumor Evaluation and Crystal Structure of Hydroxyurea Derivatives

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