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PubMed2000

Evaluation of the hydroxylamine Tempol-H as an in vivo radioprotector.

Nitroxides are stable free radical compounds that protect against the toxicity of reactive oxygen species in vitro and in vivo. Tempol (Aldrich, Milwaukee, WI, USA) is a cell-permeable hydrophilic nitroxide and has been shown to be an in vitro and in vivo radioprotector. The limitations of Tempol as a systemic radioprotector are that it causes substantial reductions in arterial blood pressure when administered intravenously and is associated with seizure activity. Furthermore, Tempol is rapidly reduced to its hydroxylamine form, Tempol-H, which limits the period of time the active form of the nitroxide is available for radioprotection. Based on initial pharmacological and blood pressure experiments performed in mice, we hypothesized that the systemic administration of Tempol-H in vivo would lead to an equilibration between Tempol and Tempol-H that would limit the toxicity of the nitroxide and provide in vivo radioprotection. Tempol-H was administered in increasing doses via an intraperitoneal route to C3H mice. The maximally tolerated dose was found to be 325 mg/kg. The whole-blood pharmacology of Tempol-H was investigated with electron paramagnetic resonance spectroscopy. These studies demonstrated the appearance of Tempol in whole blood immediately after intraperitoneal injection, suggesting that rapid oxidation of Tempol-H to Tempol takes place in vivo. Although the peak concentration of Tempol in whole blood after administration of Tempol-H did not reach the same levels as those observed when Tempol is administered, the whole-blood levels of Tempol were similar by 10 min after injection. Tempol-H provided protection against the lethality of whole-body radiation in C3H mice at 30 d with a dose modification factor of 1.3, which is similar to the results obtained with Tempol. Hemodynamic measurements in C3H mice after intravenous injection showed that Tempol-H produced little effect on blood pressure or pulse compared with Tempol. Tempol-H is a systemic in vivo radioprotector of C3H mice and is associated with less hemodynamic toxicity than Tempol.

Animals↗
PubMed2000

N-formyl hydroxylamine containing dipeptides: generation of a new class of vasopeptidase inhibitors.

Four primary zinc-binding pharmacophores (thiols, carboxylates, phosphorus acids, and hydroxamates) have been utilized in generating inhibitors of zinc metalloproteases such as ACE, NEP, the MMPs, and ECE. Although compounds which inhibit the activity of both ACE and NEP (vasopeptidase inhibitors, VPIs) have been reported which incorporate a thiol, carboxylate, or phosphorus acid pharmacophore, the generation of hydroxamate based vasopeptidase inhibitors has remained elusive. Herein we report the first potent vasopeptidase inhibitors which were generated from the incorporation of conformationally restricted dipeptide mimetics to an N-formyl hydroxylamine zinc-binding group. Compounds such as 13c and 13d are among the most potent in this series, exhibiting in vitro activity comparable to other classes of inhibitors.

Dipeptides↗
PubMed2003

Hydroxylamine potentiates the effect of low dose hydrogen peroxide in glioma cells independent of p53.

We had earlier shown that higher concentration of hydrogen peroxide (H(2)O(2)) induced p53-dependent apoptosis in glioma cell line with wild type p53 but had minimal effect on cells with mutated p53. Here we show a potentiating effect of hydroxylamine (HA), an inhibitor of catalase, on a nontoxic dose of H(2)O(2) in glioma cells. HA sensitized both p53 wild type and mutated glioma cells to 0.25 mM H(2)O(2). Potentiating effect of HA was independent of p53. Higher levels of reactive oxygen species (ROS) generation were observed in cells treated with HA+H(2)O(2) as compared to cells treated with each component alone in both the cell lines. Dimethyl sulfoxide (DMSO) protected cells. Cytosolic cytochrome c and activated caspase 3 were detected at 4h. The results suggest that higher levels of intracellular ROS, generated by HA+H(2)O(2) act as a molecular switch in activating a rapidly acting p53-independent mitochondrial apoptotic pathway.

Caspase 3↗
PubMed2002

Anharmonic vibrational spectra of hydroxylamine and its 15N, 18O, and deuterium substituted analogs.

Vibrational self-consistent field (VSCF) and correlation-corrected vibrational self-consistent field (CC-VSCF) methods were used to compute the anharmonic frequencies of fundamentals, overtones, and combination transitions of natural abundance hydroxylamine, 15NH2OH, NH2(18)OH, ND2OD, ND2OH, and NH2OD isotopomers at second order Møller-Plesset perturbation theory (MP2) in basis sets of triple-zeta quality. Frequencies of the fundamental transitions observed in the gas phase spectrum were reproduced by CC-VSCF treatment within 20 cm(-1) in TZV(d,p) and TZV(2d,2p) basis sets, and the change of basis set composition had only minor effect on the frequencies of the computed fundamentals. CC-VSCF computed wave numbers of overtone and combination transitions were typically within 1-40 cm(-1) of the gas phase band positions, except for those resulting from multiple excitations of v2, v3, and v7 fundamentals, because of a strong mutual coupling between these modes. Integral transition intensities calculated at MP2 level closely followed those of experimental spectrum, including intensity decrease in v1, 2v1, 3v1 progression, and 30-fold intensity increase of 2v8 in respect to that of v8 fundamental. The frequency of the OH torsional fundamental was found to be strongly dependent on the mode-mode interaction potential among v9 and v1, v7, v2, v4, v5 modes. Band shifts resulting from 15N, 18O and complete 2H substitutions were reproduced almost quantitatively by CC-VSCF computation in TZV(d,p) basis. Computed anharmonic isotope frequency shifts were different from those obtained in the harmonic approximation and no scaling procedure seemed capable of performing their interchange.

Biophysical Phenomena↗
PubMed1992

Reduction of the small subunit of Escherichia coli ribonucleotide reductase by hydrazines and hydroxylamines.

Each polypeptide chain of protein R2, the small subunit of ribonucleotide reductase from Escherichia coli, contains a stable tyrosyl radical and an antiferromagnetically coupled diferric center. Recent crystallographic studies [Nordlund, P., Eklund, H., & Sjöberg, B.-M. (1990) Nature 345, 593-598] have shown that both the radical and the diiron site are deeply buried inside the protein and thus strongly support the hypothesis of long-range electron-transfer processes within protein R2. This study shows that monosubstituted hydrazines and hydroxylamines are able to reduce the tyrosyl radical and the ferric ions, under anaerobic conditions. It allows characterization of the site from which those compounds transfer their electrons to the iron/radical center. The efficiency of any given reducing agent is not solely governed by its redox potential but also by its size, its charge, and its hydrophobicity. We suggest, as a possible alternative to the long-range electron-transfer hypothesis, that conformational flexibility of the polypeptide chain might exist in solution and allow small molecules to penetrate the protein and react with the iron/radical center. This study also shows that two reduction mechanisms are possible, depending on which center, the radical or the metal, is reduced first. Full reduction of protein R2 yields reduced R2, characterized by a normal tyrosine residue and a diferrous center. Both the radical and the diferric center are regenerated from reduced R2 by reaction with oxygen, while only the diferric center is formed by reaction with hydrogen peroxide.

Electron Spin Resonance Spectroscopy↗
PubMed1986

Electrophilic amination of a single methionine residue located at the active site of D-amino acid oxidase by O-(2,4-dinitrophenyl)hydroxylamine.

O-(2,4-Dinitrophenyl)hydroxylamine is a rapid active-site-directed inhibitor of D-amino acid oxidase: modification results in specific incorporation of an amine group into an accessible nucleophilic residue with concomitant release of 2,4-dinitrophenol. The reaction is prevented by the competitive inhibitor benzoate, indicating an active-site-directed reaction. A stoichiometry of 1-1.5 mol of amine residues per enzyme bound flavin adenine dinucleotide monomer was observed at pH 7.0. Amino acid and sequence analyses show that His-217 is not the target of the modification reaction. Dependence of the modification on pH, model studies on functional groups present on amino acids, and thiolysis studies on aminated enzyme collectively indicate that the modification is located on a methionine residue at or near the active site of the enzyme. Aminated enzyme, although spectrally similar to native enzyme, exhibits a 7-9-nm blue shift in the 455-nm flavin absorption. Benzoate perturbs the spectrum of aminated enzyme, but binding relative to native enzyme is much weaker (Kd ca. 300 times greater at pH 8.0).

Animals↗
PubMed1987

Identification of methionine-110 as the residue covalently modified in the electrophilic inactivation of D-amino-acid oxidase by O-(2,4-dinitrophenyl) hydroxylamine.

The reaction of O-(2,4-dinitrophenyl)hydroxylamine with D-amino-acid oxidase leads to complete inactivation which can be protected against by the competitive inhibitor benzoate [D'Silva, C., Williams, C. H., Jr., & Massey, V. (1986) Biochemistry 25, 5602-5608]. The residue modified has been identified as methionine-110. Differential high-performance liquid chromatography mapping of tryptic digests of D-amino-acid oxidase modified in the absence and presence of benzoate allows the isolation of a single methionine-containing tryptic peptide corresponding to residues 100-115 and referred to as T6-T7. In unmodified enzyme, the bond involving Arg-108 is readily cleaved and T6 and T7 are isolated. Brief treatment of peptide T6-T7 with carboxypeptidase Y released residues 112-115, and the residual peptide was isolated in good yield. Further treatment of this peptide (residues 100-111) with carboxypeptidase Y released Val and an unknown amino acid that comigrated with synthetically prepared S-aminomethionine sulfonium salt. The unknown compound and S-aminomethionine break down to methionine on treatment with dithiothreitol.

Amino Acids↗
PubMedDate not supplied

Polymer-supported N-derivatized, o-linked hydroxylamine for concurrent solid-phase synthesis of diverse N-alkyl and N-H hydroxamates.

We describe parallel/combinatorial, solid-phase, supported synthesis of diverse hydroxamates using a common intermediate, an N-derivatized, O-linked hydroxylamine. The method allows the concurrent synthesis of both N-alkyl and N-H hydroxamates and is compatible with a wide range of chemical transformations. The synthesis of NH hydroxamates includes protection of the nitrogen with a 2,4-dimethoxybenzyl group at the stage of polymer-supported benzyloxyamine. The protecting group eliminates side reactions caused by the presence of a free hydroxamate NH group and is simultaneously removed during cleavage of target compounds from the solid support. The chemical route has been thoroughly tested on model compounds with several linkers, and a high yield and purity synthesis of more than 50 hydroxamates, designed to inhibit cell proliferation of breast cancer cell lines, is described.

Antineoplastic Agents↗
PubMed2003

Selective one-electron reduction of Nitrosomonas europaea hydroxylamine oxidoreductase with nitric oxide.

Hydroxylamine oxidoreductase (HAO) from the autotrophic bacterium Nitrosomonas europaea catalyzes the 4-e- oxidation of NH2-OH to NO2-. The e- are transferred from NH2OH to an unusual 5-coordinate heme known as P460, which is the active site of HAO, and from there to an array of seven c-type hemes. NO., generated by laser flash photolysis of N,N'-bis(carboxymethyl)-N,N'-dinitroso-1,4-phenylenediamine, is found to act as a 1-e- donor to HAO. Most likely NO. binds P460 to yield a [Fe(NO)]6 moiety, which then hydrolyzes to give the reduced enzyme and NO2-. The [Fe(NO)]6 moiety is also a plausible final intermediate in the oxidation of NH2OH.

Catalysis↗
PubMed1996

Dibenzoxepinone hydroxylamines and hydroxamic acids: dual inhibitors of cyclooxygenase and 5-lipoxygenase with potent topical antiinflammatory activity.

Hydroxylamine and hydroxamic acid derivatives of a known nonsteroidal antiinflammatory dibenzoxepine series display both cyclooxygenase (CO) and 5-lipoxygenase (5-LO) inhibitory properties. Many of these new dual CO/5-LO inhibitors also exhibit potent topical antiinflammatory activity in the arachidonic acid-induced murine ear edema model. On the basis of their promising profile of in vitro and in vivo activities, hydroxamic acids 24h, 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-++ +methylpropanamide (HP 977), and 25, 3-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-hydroxy-N- methylpropanamide (P10294), were selected as developmental candidates for the topical treatment of inflammatory skin disorders.

3T3 Cells↗
PubMed2006

Copper-catalyzed electrophilic amination of organozinc nucleophiles: documentation of O-benzoyl hydroxylamines as broadly useful R2N(+) and RHN(+) synthons.

[reaction: see text] This paper details new copper-catalyzed electrophilic amination reactions of diorganozinc reagents using O-benzoyl hydroxylamines as electrophilic nitrogen sources that may be accessed in one step. Simple and functionalized aryl, heteroaryl-, benzyl, n-alkyl, sec-alkyl, and tert-alkyl nucleophiles couple with R2NOC(O)Ph and RHNOC(O)Ph reagents in the presence of catalytic quantities of copper salts to provide tertiary and secondary amines, respectively, in generally good yields. In many cases, the product may be isolated analytically pure after a simple extractive workup. The amination process is shown to tolerate a significant degree of steric demand. The amination of nominally unreactive C(aryl)-H bonds via a sequential directed ortho metalation/transmetalation/catalytic amination reaction sequence is detailed. The direct Cu-catalyzed amination of Grignard reagents using cocatalysis by ZnCl2 is described.

Amination↗
PubMed2006

Synthesis of alpha-amino acid precursors directly from aldehydes using masked acyl cyanide reagents and N,O-dialkylated hydroxylamines.

A synthetic methodology for the synthesis of alpha-amino acid precursors directly from the corresponding aldehydes using N,O-dialkylated hydroxylamines and masked acyl cyanide (MAC) reagents was developed. The one-pot reaction can be carried out under mild conditions and without a separate purification step of the imino species. The method was applied to the synthesis of optically pure (+)-4-methylphenylglycine and the derivatives by using an Abiko-Masamune's tricyclic 1,2-oxazolidine as the chiral auxiliary.

Acetonitriles↗
PubMed1999

N,O-Bis(trifluoroacetyl)hydroxylamine as a useful electrophilic nitrogen source: catalytic synthesis of N-(trifluoroacetyl)sulfilimines.

[formula: see text] In the presence of catalytic quantites of Cu(OTf)2 the novel hydroxamic acid anhydride salt functions competently in the trifluoroacetamidation of sulfides to afford N-(trifluoroacetyl)sulfilimines. The salient features of this salt include its ease of synthesis from the inexpensive, commercially available starting materials trifluoroacetic anhydride and hydroxylamine hydrochloride.

Acetamides↗
PubMed1999

Synthesis of a chemiluminescent acridinium hydroxylamine (AHA) for the direct detection of abasic sites in DNA.

[structure: see text] The synthesis of a chemiluminescent acridinium hydroxylamine (AHA) for the direct detection of abasic sites in damaged nucleic acids is described. The reagent reacts readily with abasic sites of damaged calf thymus DNA generated in a time-dependent manner under acid/heat depurination conditions. Preliminary results indicate the sensitivity of the direct chemiluminescent detection format is approximately 0.1 abasic sites detected per 10(6) nucleotides using as little as 200 ng of DNA.

Acridines↗
PubMed2002

Inhibition of enzymes of polyamine biosynthesis by substrate-like O-substituted hydroxylamines.

The biogenic amines spermine, spermidine, and putrescine are essential factors of cell growth and differentiation. To inhibit pyridoxal-5'-phosphate dependent ornithine decarboxylase and pyruvate dependent S-adenosylmethionine decarboxylase, key enzymes of polyamine biosynthesis, a system of substrate-like O-substituted hydroxylamines is suggested. The best of these compounds were active at nanomolar concentrations. High potency and specificity of this type of inhibitors are discussed in terms of structural similarity of E-I and E-S complexes.

Adenosylmethionine Decarboxylase↗