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Archives of Biochemistry and Biophysics Jul 2020Hydropersulfides are reported to be good biological reductants, superior to thiols and akin to selenols. As such, they have been previously shown to reduce...
Hydropersulfides are reported to be good biological reductants, superior to thiols and akin to selenols. As such, they have been previously shown to reduce metalloproteins such as ferric myoglobin and ferric cytochrome c to their ferrous forms under conditions where little or no reduction from corresponding thiols is observed. Not surprisingly, the reduction of ferric myoglobin to ferrous myoglobin under aerobic conditions results in the generation of oxymyoglobin (dioxygen bound ferrous myoglobin). Previous studies have demonstrated that oxymyoglobin can also act as an oxidant with highly reducing species such as hydroxylamine and ascorbate. Considering the reducing properties of hydropersulfides, it is possible that they can also react with oxymyoglobin similarly to hydroxylamine or ascorbate. Herein, this reaction is examined and indeed hydropersulfides are found to react with oxymyoglobin similarly to other reducing species leading to a fleeting ferric myoglobin which is rapidly reduced to the ferrous form also by hydropersulfide.
Topics: Animals; Ascorbic Acid; Cattle; Horses; Hydroxylamine; Models, Chemical; Myoglobin; Oxidation-Reduction; Oxygen; Penicillamine; Sulfides
PubMed: 32360749
DOI: 10.1016/j.abb.2020.108391 -
Organic & Biomolecular Chemistry May 2020O-Cyclopropyl hydroxylamines, now accessible via a novel and scalable synthetic route, have been demonstrated to be bench-stable and practical precursors for the...
O-Cyclopropyl hydroxylamines, now accessible via a novel and scalable synthetic route, have been demonstrated to be bench-stable and practical precursors for the synthesis of N-heterocycles via a di-heteroatom [3,3]-sigmatropic rearrangement. In order to study the reactivity of these compounds in depth, a robust synthesis of both ring-substituted and ring-unsubstituted O-cyclopropyl hydroxylamines has been developed. Metal-free conditions for the facile N-arylation of these precursors were also identified. It was found that the N-arylated O-cyclopropyl hydroxamates can efficiently undergo a one-pot [3,3]-sigmatropic rearrangement/cyclization/rearomatization cascade under base-mediated conditions to furnish a structurally diverse set of substituted tetrahydroquinolines.
Topics: Cyclization; Heterocyclic Compounds; Hydroxylamine; Hydroxylamines; Molecular Structure; Quinolines; Stereoisomerism
PubMed: 32319502
DOI: 10.1039/d0ob00611d -
Biochemistry. Biokhimiia Dec 2013The biogenic polyamines spermine, spermidine, and their precursor putrescine are present in micro-to-millimolar concentrations in all cell types and are vitally... (Review)
Review
The biogenic polyamines spermine, spermidine, and their precursor putrescine are present in micro-to-millimolar concentrations in all cell types and are vitally important for their normal growth. High intracellular content of spermine and spermidine determines the multiplicity of the cellular functions of the polyamines. Many of these functions are not well characterized at the molecular level, ensuring the ongoing development of this field of biochemistry. Tumor cells have elevated polyamine level if compared with normal cells, and this greatly stimulates the search for new opportunities to deplete the intracellular pool of spermine and spermidine resulting in decrease in cell growth and even cell death. O-Substituted hydroxylamines occupy their own place among chemical regulators of the activity of the enzymes of polyamine metabolism. Varying the structure of the alkyl substituent made it possible to obtain within one class of chemical compounds highly effective inhibitors and regulators of the activity of all the enzymes of putrescine, spermine and spermidine metabolism (with the exception of FAD-dependent spermine oxidase and acetylpolyamine oxidase), effectors of the polyamine transport system, and even actively transported in cells "proinhibitor" of ornithine decarboxylase. Some principles for the design of specific inhibitors of these enzymes as well as the peculiarities of cellular effects of corresponding O-substituted hydroxylamines are discussed.
Topics: Animals; Humans; Hydroxylamine; Ornithine Decarboxylase; Oxidoreductases Acting on CH-NH Group Donors; Spermidine; Spermine; Polyamine Oxidase
PubMed: 24490733
DOI: 10.1134/S0006297913130051 -
Chemical Communications (Cambridge,... Sep 2022Electrophilic aminating reagents have seen a renaissance in recent years as effective nitrogen sources for the synthesis of unprotected amino functionalities. Based on... (Review)
Review
Electrophilic aminating reagents have seen a renaissance in recent years as effective nitrogen sources for the synthesis of unprotected amino functionalities. Based on their reactivity, several noble and non-noble transition metal catalysed amination reactions have been developed. These include the aziridination and difunctionalisation of alkenes, the amination of arenes as well as the synthesis of aminated sulfur compounds. In particular, the use of hydroxylamine-derived (N-O) reagents, such as PONT (PivONHOTf), has enabled the introduction of unprotected amino groups on various different feedstock compounds, such as alkenes, arenes and thiols. This strategy obviates undesired protecting-group manipulations and thus improves step efficiency and atom economy. Overall, this feature article gives a recent update on several reactions that have been unlocked by employing versatile hydroxylamine-derived aminating reagents, which facilitate the generation of unprotected primary, secondary and tertiary amino groups.
Topics: Alkenes; Amines; Hydroxylamine; Hydroxylamines; Indicators and Reagents; Molecular Structure
PubMed: 35993918
DOI: 10.1039/d2cc02431d -
ACS Chemical Biology Nov 2020Reactive electrophilic intermediates such as coenzyme A esters play central roles in metabolism but are difficult to detect with conventional strategies. Here, we...
Reactive electrophilic intermediates such as coenzyme A esters play central roles in metabolism but are difficult to detect with conventional strategies. Here, we introduce hydroxylamine-based stable isotope labeling to convert reactive electrophilic intermediates into stable derivatives that are easily detectable LC-MS. In the model system , parallel treatment with NHOH and NHOH revealed >1000 labeled metabolites, e.g., derived from peptide, fatty acid, and ascaroside pheromone biosyntheses. Results from NHOH treatment of a pheromone biosynthesis mutant, , suggested upregulation of thioesterase activity, which was confirmed by gene expression analysis. The upregulated thioesterase contributes to the biosynthesis of a specific subset of ascarosides, determining the balance of dispersal and attractive signals. These results demonstrate the utility of NHOH labeling for investigating complex biosynthetic networks. Initial results with and human cell lines indicate applicability toward uncovering reactive metabolomes in diverse living systems.
Topics: Animals; Aspergillus; Biosynthetic Pathways; Caenorhabditis elegans; Cell Line; Chromatography, Liquid; Humans; Hydroxylamine; Isotope Labeling; Mass Spectrometry; Metabolome; Metabolomics
PubMed: 33074644
DOI: 10.1021/acschembio.0c00706 -
Accounts of Chemical Research Oct 2018Proton-coupled electron transfer (PCET) covers a wide range of reactions involving the transfer(s) of electrons and protons. The best-known PCET reaction, hydrogen atom...
Proton-coupled electron transfer (PCET) covers a wide range of reactions involving the transfer(s) of electrons and protons. The best-known PCET reaction, hydrogen atom transfer (HAT), has been studied in detail for more than a century. HAT is generally described as the concerted transfer of a hydrogen atom (H ≡ H + e) from one group to another, Y + H-X → Y-H + X, but a strict definition of HAT has been difficult to establish. Distinctions are more challenging when the transfer of "H" involves e and H that transfer to/from spatially distinct sites or even completely separate reagents (multiple-site concerted proton-electron transfer, MS-CPET). MS-CPET reactivity is increasingly proposed in biological and synthetic contexts, and some reactions typically described as HAT more resemble MS-CPET. Despite that HAT and MS-CPET reactions "look different," we argue here that these reactions lie on a reactivity continuum, and that they are governed by many of the same key parameters. This Account walks the reader across this PCET reactivity continuum, using a series of studies to show the strong similarities of reactions that move protons and electrons in seemingly different ways. To prepare for our stroll, we describe the thermochemical and kinetic frameworks for HAT and MS-CPET. The driving force for a solution HAT reaction is most easily discussed as the difference in the bond dissociation free energies (BDFEs) of the reactants and products. BDFEs can be analyzed as sums of electron and proton transfer steps and can therefore be obtained from p K and E° values. Even though MS-CPET reactions do not make and break H-X bonds in the same way as HAT, the same thermochemical description can be used with the introduction of an effective BDFE (BDFE). The BDFE of a reductant/acid pair is the free energy of that pair to form H, which can be obtained from p K and E° values in an analogous fashion to a standard BDFE. When the PCET thermochemistry is known, HAT and PCET rate constants can be understood and often predicted using linear free energy relationships (the Brønsted catalysis law) and Marcus theory type approaches. After this background, we walk the reader through a continuum of PCET reactivity. Our journey begins with a study of metal-mediated HAT from hydrocarbon substrates to a metal-oxo complex and travels to the MS-CPET end of the reactivity spectrum, involving the transfer of H and e from the hydroxylamine TEMPOH to two completely separate molecules. These examples, and those in between, are all analyzed within the same thermodynamic and kinetic framework. A description of the first examples of MS-CPET with C-H bonds uses the same framework and highlights the importance of hydrogen bonding and preorganization. The examples and analyses show that the reactions along the PCET continuum are more similar than they are different, and that attempts to divide these reactions into subcategories can obscure much of the essential chemistry. We hope that developing the many common features of these reactions will help experts and newcomers alike to explore exciting new territories in PCET reactivity.
Topics: Carbon; Coordination Complexes; Electron Transport; Electrons; Hydrogen; Hydrogen Bonding; Hydroxylamine; Kinetics; Oxidation-Reduction; Phenols; Protons; Ruthenium; Thermodynamics
PubMed: 30234963
DOI: 10.1021/acs.accounts.8b00319 -
Biological & Pharmaceutical Bulletin Nov 2002The anti-inflammatory activities of several novel oximes and O-acyl oximes that we synthesized have been reported based on carrageenan-induced rat foot-pad swelling...
The anti-inflammatory activities of several novel oximes and O-acyl oximes that we synthesized have been reported based on carrageenan-induced rat foot-pad swelling assay and histamine-induced rat vascular permeability assay. A cyclooxygenase (COX)-1 inhibitory effect has also been reported for 4'-piperidinoacetophenone and 4'-morpholinoacetophenone oximes and their O-acyl derivatives. To further search for more effective non-steroidal anti-inflammatory or anti-allergic drugs, 1-hydroxylamino-1-(4'-piperidinophenyl) ethane (P-HA) and 1-hydroxylamino-1-(4'-morpholinophenyl) ethane (M-HA) were synthesized from the corresponding oximes with sodium cyanoborohydride, and N,O-diacetyl hydroxylamines (P-HA-Ac and M-HA-Ac) were prepared from these hydroxylamines using acetyl chloride. These hydroxylamines and N,O-diacetyl hydroxylamines clearly exhibited inhibitory effects on mouse carrageenan-induced foot-pad swelling induced by oral administration (150, 37.5 mg/kg). An oral dose of P-HA-Ac (150 mg/kg) significantly inhibited the mouse anaphylactic reaction to ovalbumin measured by the abdominal wall (AW) method. Percutaneous administration of P-HA and M-HA significantly inhibited 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity reaction (type IV) in mice at a dose of 0.5 and 0.1 mg/ear, respectively. All tested hydroxylamines and N,O-diacetyl hydroxylamines clearly inhibited both COX-1 and COX-2 enzyme activities with IC(50) values of 1.9-28.7 and 1.6-2.9 micro M against COX-1 and COX-2, respectively. Hydroxylamines (P-HA and M-HA) also showed a 5-lipoxygenase inhibitory effect.
Topics: Animals; Anti-Allergic Agents; Anti-Inflammatory Agents, Non-Steroidal; Edema; Hydroxylamine; Male; Mice; Mice, Inbred BALB C; Pain Measurement; Rats; Rats, Sprague-Dawley
PubMed: 12419955
DOI: 10.1248/bpb.25.1436 -
Antimicrobial Agents and Chemotherapy Feb 2020is an obligate intracellular protozoan parasite and a successful parasitic pathogen in diverse organisms and host cell types. Hydroxylamine (HYD) and...
is an obligate intracellular protozoan parasite and a successful parasitic pathogen in diverse organisms and host cell types. Hydroxylamine (HYD) and carboxymethoxylamine (CAR) have been reported as inhibitors of aspartate aminotransferases (AATs) and interfere with the proliferation in Therefore, AATs are suggested as drug targets against The genome encodes only one predicted AAT in both type I strain RH and type II strain PLK. However, the effects of HYD and CAR, as well as their relationship with AAT, on remain unclear. In this study, we found that HYD and CAR impaired the lytic cycle of , including the inhibition of invasion or reinvasion, intracellular replication, and egress. Importantly, HYD and CAR could control acute toxoplasmosis Further studies showed that HYD and CAR could inhibit the transamination activity of rAAT However, our results confirmed that deficiency of AAT in both RH and PLK did not reduce the virulence in mice, although the growth ability of the parasites was affected HYD and CAR could still inhibit the growth of AAT-deficient parasites. These findings indicated that HYD and CAR inhibition of growth and control of toxoplasmosis can occur in an AAT-independent pathway. Overall, further studies focusing on the elucidation of the mechanism of inhibition are warranted. Our study hints at new substrates of HYD and CAR as potential drug targets to inhibit growth.
Topics: Aminooxyacetic Acid; Animals; Antiprotozoal Agents; Aspartate Aminotransferases; Cell Line; Chlorocebus aethiops; Female; Fibroblasts; Gene Expression; Genes, Reporter; Green Fluorescent Proteins; Humans; Hydroxylamine; Life Cycle Stages; Mice; Mice, Inbred BALB C; Parasitic Sensitivity Tests; Protozoan Proteins; Toxoplasma; Toxoplasmosis; Vero Cells
PubMed: 31907178
DOI: 10.1128/AAC.01889-19 -
Chemical Research in Toxicology Jun 2013Many aromatic amines and heterocyclic aromatic amines (HAAs) are known carcinogens for animals, and there is also strong evidence of some in human cancer. The activation...
Many aromatic amines and heterocyclic aromatic amines (HAAs) are known carcinogens for animals, and there is also strong evidence of some in human cancer. The activation of these compounds, including some arylamine drugs, involves N-hydroxylation, usually by cytochrome P450 enzymes (P450) in Family 1 (1A2, 1A1, and 1B1). We previously demonstrated that the bioactivation product of the anticancer agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203), an N-hydroxylamine, can be reduced by P450 2S1 to its amine precursor under anaerobic conditions and, to a lesser extent, under aerobic conditions [Wang, K., and Guengerich, F. P. (2012) Chem. Res. Toxicol. 25, 1740-1751]. In the study presented here, we tested the hypothesis that P450 2S1 is involved in the reductive biotransformation of known carcinogenic aromatic amines and HAAs. The N-hydroxylamines of 4-aminobiphenyl (4-ABP), 2-naphthylamine (2-NA), and 2-aminofluorene (2-AF) were synthesized and found to be reduced by P450 2S1 under both anaerobic and aerobic conditions. The formation of amines due to P450 2S1 reduction also occurred under aerobic conditions but was less apparent because the competitive disproportionation reactions (of the N-hydroxylamines) also yielded amines. Further, some nitroso and nitro derivatives of the arylamines could also be reduced by P450 2S1. None of the amines tested were oxidized by P450 2S1. These results suggest that P450 2S1 may be involved in the reductive detoxication of several of the activated products of carcinogenic aromatic amines and HAAs.
Topics: Cytochrome P-450 Enzyme System; Heterocyclic Compounds; Humans; Hydroxylamines; Molecular Structure; Oxidation-Reduction
PubMed: 23682735
DOI: 10.1021/tx400139p -
PloS One 2018Glycan analysis may result in exploitation of glycan biomarkers and evaluation of heterogeneity of glycosylation of biopharmaceuticals. For N-linked glycan analysis, we...
Glycan analysis may result in exploitation of glycan biomarkers and evaluation of heterogeneity of glycosylation of biopharmaceuticals. For N-linked glycan analysis, we investigated alkaline hydrolysis of the asparagine glycosyl carboxamide of glycoproteins as a deglycosylation reaction. By adding hydroxylamine into alkaline de-N-glycosylation, we suppressed the degradation of released glycans and obtained a mixture of oximes, free glycans, and glycosylamines. The reaction was completed within 1 h, and the mixture containing oximes was easily tagged with 2-aminobenzamide by reductive amination. Here, we demonstrated N-linked glycan analysis using this method for a monoclonal antibody, and examined whether this method could liberate glycans without degradation from apo-transferrin containing NeuAc and NeuGc and horseradish peroxidase containing Fuc α1-3 GlcNAc at the reducing end. Furthermore, we compared glycan recoveries between conventional enzymatic glycan release and this method. Increasing the reaction temperature and reaction duration led to degradation, whereas decreasing these parameters resulted in lower release. Considering this balance, we proposed to carry out the reaction at 80°C for 1 h for asialo glycoproteins from mammals and at 50°C for 1 h for sialoglycoproteins.
Topics: Amination; Animals; Antibodies, Monoclonal; Apoproteins; Cattle; Chromatography, Liquid; Glycoproteins; Glycosylation; Horseradish Peroxidase; Hydrolysis; Hydroxylamine; Methylation; Oximes; Polysaccharides; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Temperature; Time Factors; Transferrin
PubMed: 29723274
DOI: 10.1371/journal.pone.0196800