The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
David Crich - One of the best experts on this subject based on the ideXlab platform.
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synthesis cytotoxicity and genotoxicity of 10 aza 9 oxakalkitoxin an n n o trisubstituted Hydroxylamine analog or hydroxalog of a marine natural product
Journal of the American Chemical Society, 2020Co-Authors: Sandeep Dhanju, Kapil Upadhyaya, Christopher A Rice, Scott D Pegan, Joseph Media, Frederick A Valeriote, David CrichAbstract:We describe the synthesis of 10-aza-9-oxakalkitoxin, an N,N,O-trisubstituted Hydroxylamine-based analog, or hydroxalog, of the cytotoxic marine natural product kalkitoxin in which the -NMe-O- moiet...
Yongmin Liang - One of the best experts on this subject based on the ideXlab platform.
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lewis acid mediated tandem reaction of propargylic alcohols with Hydroxylamine hydrochloride to give α β unsaturated amides and alkenyl nitriles
ChemInform, 2016Co-Authors: Xianrong Song, Xinxing Wu, Jia Wang, Yongmin LiangAbstract:New strategies extend the application of Hydroxylamine hydrochloride to the chemistry of propargylic alcohols.
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lewis acid mediated tandem reaction of propargylic alcohols with Hydroxylamine hydrochloride to give α β unsaturated amides and alkenyl nitriles
Journal of Organic Chemistry, 2015Co-Authors: Xianrong Song, Xinxing Wu, Jia Wang, Yongmin LiangAbstract:We have developed a highly selective method for the synthesis of α,β-unsaturated amides and alkenyl nitriles from readily available propargylic alcohols. The reaction proceeded smoothly under the neutral conditions with Hydroxylamine hydrochloride (NH2OH·HCl) as the nitrogen source. The development of these new strategies has significantly extended the application of Hydroxylamine hydrochloride to the chemistry of propargylic alcohols. Moreover, both secondary and tertiary alcohols have been highly regioselectively transformed to the desired products with good functional group compatibility.
Lauren A Trepanier - One of the best experts on this subject based on the ideXlab platform.
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dapsone associated methemoglobinemia in a patient with slow nat2 5b haplotype and impaired cytochrome b5 reductase activity
The Journal of Clinical Pharmacology, 2012Co-Authors: Mahmoud Abouraya, James C Sacco, Kristie Hayes, Sajeve Samuel Thomas, Craig S Kitchens, Lauren A TrepanierAbstract:Dapsone (4,4′-diaminodiphenylsulfone; DDS) is a sulfone antimicrobial used to treat leprosy, malaria, and inflammatory dermatoses and to prevent and treat opportunistic infections in immunocompromised patients, particularly those who cannot tolerate sulfonamide antimicrobials.1 However, dapsone can lead to dose-dependent hematologic toxicity and is the most commonly recognized cause of acquired methemoglobinemia in human patients.2 The Hydroxylamine metabolite of dapsone oxidizes the iron moiety of hemoglobin,3 which leads to increased levels of methemoglobin, impaired oxygen delivery, and cyanosis. Dapsone Hydroxylamine is generated by CYP2C9 and CYP2C19, with minor contributions from other P450s.4,5 A rapid activity variant for CYP2C19 (CYP2C19*17) has been reported6 but not for CYP2C9. Dapsone Hydroxylamine is detoxified by cytochrome b5 (b5) and its electron donor, cytochrome b5 reductase (b5R),7 which are expressed in blood, liver, and other tissues. This reduction pathway converts the Hydroxylamine back to the parent dapsone. Dapsone itself is inactivated and eliminated following N-acetylation by the enzyme NAT2 in the liver,8 and impaired N-acetylation activity is a risk factor for hematologic and neurologic toxicity from dapsone.9,10 However, genotypic analysis of the CYP2C19, NAT2, and b5/b5R pathways has not been performed in the setting of dapsone-associated methemoglobinemia. This report describes a patient who developed methemoglobinemia at prophylactic dosages of dapsone, for which we characterized wild-type alleles at the CYP2C19*17 loci, but low activity of the b5/b5R pathway along with low expression of the CYB5A gene encoding b5, and a homozygous slow NAT2*5B haplotype, both of which may have contributed to defective dapsone detoxification.
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cytochrome b5 and nadh cytochrome b5 reductase genotype phenotype correlations for Hydroxylamine reduction
Pharmacogenetics and Genomics, 2010Co-Authors: James C Sacco, Lauren A TrepanierAbstract:Objectives NADH cytochrome b5 reductase (b5R) and cytochrome b5 (b5) catalyze the reduction of sulfamethoxazole Hydroxylamine (SMX-HA), which can contribute to sulfonamide hypersensitivity, to the parent drug sulfamethoxazole. Variability in Hydroxylamine reduction could thus play a role in adverse drug reactions. The aim of this study was to characterize variability in SMX-HA reduction in 111 human livers, and investigate its association with single nucleotide polymorphisms (SNPs) in b5 and b5R cDNA.
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nadh cytochrome b5 reductase and cytochrome b5 catalyze the microsomal reduction of xenobiotic Hydroxylamines and amidoximes in humans
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Joseph R Kurian, Sunil U Bajad, Jackie L Miller, Nathaniel A Chin, Lauren A TrepanierAbstract:Hydroxylamine metabolites, implicated in dose-dependent and idiosyncratic toxicity from arylamine drugs, and amidoximes, used as pro-drugs, are metabolized by an as yet incompletely characterized NADH-dependent microsomal reductase system. We hypothesized that NADH cytochrome b 5 reductase and cytochrome b 5 were responsible for this enzymatic activity in humans. Purified human soluble NADH cytochrome b 5 reductase and cytochrome b 5, expressed in Escherichia coli , efficiently catalyzed the reduction of sulfamethoxazole Hydroxylamine, dapsone Hydroxylamine, and benzamidoxime, with apparent K m values similar to those found in human liver microsomes and specific activities ( V max) 74 to 235 times higher than in microsomes. Minimal activity was seen with either protein alone, and microsomal protein did not enhance activity other than additively. All three reduction activities were significantly correlated with immunoreactivity for cytochrome b 5 in individual human liver microsomes. In addition, polyclonal antibodies to both NADH cytochrome b 5 reductase and cytochrome b 5 significantly inhibited reduction activity for sulfamethoxazole Hydroxylamine. Finally, fibroblasts from a patient with type II hereditary methemoglobinemia (deficient in NADH cytochrome b 5 reductase) showed virtually no activity for Hydroxylamine reduction, compared with normal fibroblasts. These results indicate a novel direct role for NADH cytochrome b 5 reductase and cytochrome b 5 in xenobiotic metabolism and suggest that pharmacogenetic variability in either of these proteins may effect drug reduction capacity.
Takashi Hirota - One of the best experts on this subject based on the ideXlab platform.
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polycyclic n heterocyclic compounds part 84 reaction of n pyrido 3 2 4 5 thieno 3 2 d pyrimidin 4 yl amidines or n pyrido 2 3 4 5 furo 3 2 d pyrimidin 4 yl amidines with Hydroxylamine hydrochloride
Journal of Heterocyclic Chemistry, 2015Co-Authors: Kensuke Okuda, Naoto Uramaru, Takashi HirotaAbstract:The reactions of nine N-(pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)amidines (3) with Hydroxylamine hydrochloride produced new cyclization products. These were formed via ring cleavage of the pyrimidine component followed by a 1,2,4-oxadiazole-forming ring closure to give N-[2-([1,2,4]oxadiazol-5-yl)thieno[2,3-b]pyridin-3-yl]formamide oximes (11). Reaction of six N-(pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-yl)amidines (12) with Hydroxylamine hydrochloride gave similar results. Effects of the newly synthesized compounds on pentosidine formation were also evaluated.
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polycyclic n heterocyclic compounds part 72 reaction of n 1 benzofuro or benzothieno 3 2 d pyrimidin 4 yl formamidine and n pyrido 2 3 d pyrimidin 4 yl formamidine derivatives with Hydroxylamine hydrochloride
Journal of Heterocyclic Chemistry, 2012Co-Authors: Kensuke Okuda, Kiyoko Tsuchie, Takashi HirotaAbstract:The reactions of N-([1]benzofuro[3,2-d]pyrimidin-4-yl)formamidines with Hydroxylamine hydrochloride gave rearranged cyclization products via ring cleavage of the pyrimidine component accompanied by a ring closure of the 1,2,4-oxadiazole to give N-[2-([1,2,4]oxadiazol-5-yl)[1]benzofuran-3-yl)formamide oximes. N-([1]Benzothieno[3,2-d]pyrimidin-4-yl)formamidines and N-(pyrido[2,3-d]pyrimidin-4-yl)formamidines with Hydroxylamine hydrochloride gave similar results.
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polycyclic n heterocyclic compounds part 67 reaction of 6 7 substituted n quinazolin 4 yl amidine derivatives with Hydroxylamine hydrochloride formation of in vitro inhibitors of pentosidine
ChemInform, 2012Co-Authors: Kensuke Okuda, Hideki Muroyama, Takashi HirotaAbstract:The synthesis of a variety of oxadiazolylphenyl formamide oxime derivatives (V), (VI), (IX) proceeds via reaction of N-(quinazolin-4-yl)amidine derivatives with Hydroxylamine hydrochloride.
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polycyclic n heterocyclic compounds part 62 reaction of n quinazolin 4 yl amidine derivatives with Hydroxylamine hydrochloride and anti platelet aggregation activity of the products
Chemical & Pharmaceutical Bulletin, 2010Co-Authors: Kensuke Okuda, Ying Xue Zhang, Hiromi Ohtomo, Takashi Hirota, Kenji SasakiAbstract:The reactions of N-(5,6,7,8-tetrahydroquinazolin-4-yl)amidines and their amide oximes with Hydroxylamine hydrochloride gave abnormal cyclization products via a ring cleavage of pyrimidine component accompanied with a ring closure of 1,2,4-oxadiazole to give N-[2-([1,2,4]oxadiazol-5-yl)cyclohexen-1-yl]formamide oximes. Similarly, N-(quinazolin-4-yl)amidines reacted with Hydroxylamine hydrochloride gave the same results. The evaluation of inhibitory activities against platelet aggregation in vitro is also described to show one derivative has potent activity.
Michael P Murphy - One of the best experts on this subject based on the ideXlab platform.
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antioxidant properties of mitotempol and its Hydroxylamine
Free Radical Research, 2009Co-Authors: Ja Trnka, Frances H Laikie, Angela Loga, Robi A J Smith, Michael P MurphyAbstract:Piperidine nitroxides such as TEMPOL have been widely used as antioxidants in vitro and in vivo. MitoTEMPOL is a mitochondria-targeted derivative of TEMPOL designed to protect mitochondria from the oxidative damage that they accumulate, but once there is rapidly reduced to its Hydroxylamine, MitoTEMPOL-H. As little is known about the antioxidant efficacy of Hydroxylamines, this study has assessed the antioxidant activity of both MitoTEMPOL and MitoTEMPOL-H. The Hydroxylamine was more effective at preventing lipid-peroxidation than MitoTEMPOL and decreased oxidative damage to mitochondrial DNA caused by menadione. In contrast to MitoTEMPOL, MitoTEMPOL-H has no superoxide dismutase activity and its antioxidant actions are likely to be mediated by hydrogen atom donation. Therefore, even though MitoTEMPOL is rapidly reduced to MitoTEMPOL-H in cells, it remains an effective antioxidant. Furthermore, as TEMPOL is also reduced to a Hydroxylamine in vivo, many of its antioxidant effects may also be mediated by its Hydroxylamine.
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a mitochondria targeted nitroxide is reduced to its Hydroxylamine by ubiquinol in mitochondria
Free Radical Biology and Medicine, 2008Co-Authors: Ja Trnka, Frances H Laikie, Robi A J Smith, Michael P MurphyAbstract:Abstract Piperidine nitroxides such as TEMPOL act as antioxidants in vivo due to their interconversion among nitroxide, Hydroxylamine, and oxoammonium derivatives, but the mechanistic details of these reactions are unclear. As mitochondria are a significant site of piperidine nitroxide metabolism and action, we synthesized a mitochondria-targeted nitroxide, MitoTEMPOL, by conjugating TEMPOL to the lipophilic triphenylphosphonium cation. MitoTEMPOL was accumulated several hundred-fold into energized mitochondria where it was reduced to the Hydroxylamine by direct reaction with ubiquinol. This reaction occurred by transfer of H from ubiquinol to the nitroxide, with the ubisemiquinone radical product predominantly dismutating to ubiquinone and ubiquinol, together with a small amount reacting with oxygen to form superoxide. The piperidine nitroxides TEMPOL, TEMPO, and butylTEMPOL reacted similarly with ubiquinol in organic solvents but in mitochondrial membranes the rates varied in the order: MitoTEMPOL > butylTEMPOL > TEMPO > TEMPOL, which correlated with the extent of access of the nitroxide moiety to ubiquinol within the membrane. These findings suggest ways of using mitochondria-targeted compounds to modulate the coenzyme Q pool within mitochondria in vivo, and indicate that the antioxidant effects of mitochondria-targeted piperidine nitroxides can be ascribed to their corresponding Hydroxylamines.
