- Synthesis of 15N-labelled nornicotine and 15N-labelled nicotine
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The synthesis of 15N-labelled nornicotine 2 and 15N-labelled nicotine 1 is described via the reductive aminocyclization of a 1,4-ketoaldehyde with a corresponding amine in the presence of sodium cyanoborohydride. Yields of 30% and 26
- Vo-Thanh, Giang,Felpin, Francois-Xavier,Nourrisson, Gilbert,Trierweiler, Michel,Robins, Richard J.,Lebreton, Jacques
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- Efficient bioelectronic actuation of the natural catalytic pathway of human metabolic cytochrome P450s
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Cytochrome (cyt) P450s comprise the enzyme superfamily responsible for human oxidative metabolism of a majority of drugs and xenobiotics. Electronic delivery of electrons to cyt P450s could be used to drive the natural catalytic cycle for fundamental investigations, stereo- and regioselective synthesis, and biosensors. We describe herein 30 nm nanometer-thick films on electrodes featuring excess human cyt P450s and cyt P450 reductase (CPR) microsomes that efficiently mimic the natural catalytic pathway for the first time. Redox potentials, electron-transfer rates, CO-binding, and substrate conversion rates confirmed that electrons are delivered from the electrode to CPR, which transfers them to cyt P450. The film system enabled electrochemical probing of the interaction between cyt P450 and CPR for the first time. Agreement of film voltammetry data with theoretical simulations supports a pathway featuring a key equilibrium redox reaction in the natural catalytic pathway between reduced CPR and cyt P450 occurring within a CPR-cyt P450 complex uniquely poised for substrate conversion.
- Krishnan, Sadagopan,Wasalathanthri, Dhanuka,Zhao, Linlin,Schenkman, John B.,Rusling, James F.
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- Identification of an N′-Nitrosonornicotine-Specific Deoxyadenosine Adduct in Rat Liver and Lung DNA
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The tobacco-specific nitrosamines N′-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered to be two of the most important carcinogens in unburned tobacco and its smoke. They readily cause tumors in laboratory animals and are classified as "carcinogenic to humans"by the International Agency for Research on Cancer. DNA adduct formation by these two carcinogens is believed to play a critical role in tobacco carcinogenesis. Among all the DNA adducts formed by NNN and NNK, 2′-deoxyadenosine (dAdo)-derived adducts have not been fully characterized. In the study reported here, we characterized the formation of N6-[4-(3-pyridyl)-4-oxo-1-butyl]-2′-deoxyadenosine (N6-POB-dAdo) and its reduced form N6-PHB-dAdo formed by NNN 2′-hydroxylation in rat liver and lung DNA. More importantly, we characterized a new dAdo adduct N6-[4-hydroxy-1-(pyridine-3-yl)butyl]-2′-deoxyadenosine (N6-HPB-dAdo) formed after NaBH3CN or NaBH4 reduction both in vitro in calf thymus DNA reacted with 5′-acetoxy-N′-nitrosonornicotine and in vivo in rat liver and lung upon treatment with NNN. This adduct was specifically formed by NNN 5′-hydroxylation. Chemical standards of N6-HPB-dAdo and the corresponding isotopically labeled internal standard [pyridine-d4]N6-HPB-dAdo were synthesized using a four-step method. Both NMR and high-resolution mass spectrometry data agreed well with the proposed structure of N6-HPB-dAdo. The new adduct coeluted with the synthesized internal standard under various LC conditions. Its product ion patterns of MS2 and MS3 transitions were also consistent with the proposed fragmentation patterns. Chromatographic resolution of the two diastereomers of N6-HPB-dAdo was successfully achieved. Quantitation suggested a dose-dependent response of the levels of this new adduct in the liver and lung of rats treated with NNN. However, its level was lower than that of 2-[2-(3-pyridyl)-N-pyrrolidinyl]-2′-deoxyinosine, a previously reported dGuo adduct that is also formed from NNN 5′-hydroxylation. The identification of N6-HPB-dAdo in this study leads to new insights pertinent to the mechanism of carcinogenesis by NNN and to the development of biomarkers of NNN metabolic activation.
- Li, Yupeng,Hecht, Stephen S.
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p. 992 - 1003
(2021/04/05)
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- Analysis and Identification of 2′-Deoxyadenosine-Derived Adducts in Lung and Liver DNA of F-344 Rats Treated with the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and Enantiomers of its Metabolite 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol
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4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are carcinogenic in animal models and are believed to play an important role in human lung carcinogenesis for cigarette smokers. Cytochrome P450-mediated metabolism of these tobacco-specific nitrosamines produces reactive species that alkylate DNA in the form of pyridyloxobutyl (POB)- or pyridylhydroxybutyl (PHB)-DNA adducts. Understanding the formation mechanism and overall levels of these adducts can potentially enhance cancer prevention methods through the identification of particularly susceptible smokers. Previous studies have identified and measured a panel of POB- and PHB-DNA base adducts of dGuo, dCyd, and Thd; however, dAdo adducts have yet to be determined. In this study, we complete this DNA adduct panel by identifying and quantifying levels of NNK- and NNAL-derived dAdo adducts in vitro and in vivo. To accomplish this, we synthesized standards for expected dAdo-derived DNA adducts and used isotope-dilution LC-ESI+-MS/MS to identify POB adducts formed in vitro from the reaction of 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc) with calf thymus DNA. Adduct levels were then quantified in lung and liver DNA of rats chronically treated with NNK or NNAL for 50 weeks using similar LC-MS detection methods. The in vitro studies identified N6-POB-dAdo and N1-POB-dIno as products of the reaction of NNKOAc with DNA, which supports our proposed mechanism of formation. Though both N6-dAdo and N1-dIno adducts were found in vitro, only N6-dAdo adducts were found in vivo, implying possible intervention by DNA repair mechanisms. Analogous to previous studies, levels of N6-POB-dAdo and N6-PHB-dAdo varied both with tissue and treatment type. Despite the adduct levels being relatively modest compared to most other POB- and PHB-DNA adducts, they may play a biological role and could be used in future studies as NNK- and NNAL-specific DNA damage biomarkers.
- Carlson, Erik S.,Upadhyaya, Pramod,Villalta, Peter W.,Ma, Bin,Hecht, Stephen S.
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p. 358 - 370
(2018/05/14)
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- Methods of using QIAPINE
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Uses of QIAPINE? to treat internal bleeding, such as subdural hematoma and subarachinoid hemorrhage, and ocular bleeding, such as such as hyphema and vitreous hemorrhage, in a subject are described. Also described are uses of QIAPINE? to treat vision loss resulting from hyphema or vitreous hemorrhage.
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(2017/06/30)
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- Microwave-assisted iridium-catalyzed synthesis of nicotine and anabasine derivatives
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Various functionalized nicotine and anabasine analogues are synthesized via a three-step sequence that exploits a microwave-assisted iridium-catalyzed N-heterocyclization of 1,4- and 1,5-diols for the construction of the pyrrolidine and piperidine ring systems. The microwave-assisted N-heterocyclization furnishes derivatives of nicotine and anabasine in good yields (50-75%) with overall yields ranging from 30-50%. Georg Thieme Verlag Stuttgart. New York.
- Apsunde, Tushar Dattu,Trudell, Mark L.
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p. 2120 - 2124
(2013/08/23)
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- Hydroxyarylketones via Ring-Opening of lactones with aryllithium reagents: An expedient synthesis of ( )-anabasamine
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The regioselective ring-opening of lactones (δ-valerolactone and γ-butyrolactone) with aryllithium reagents is reported for the construction of a series of δ-hydroxy aryl ketones and γ-hydroxy aryl ketones. Application of this method for the expeditious syntheses of ( )-anabasamine and its nicotine-related analogue are also described.
- Miao, Lei,Dimaggio, Stassi C.,Trudell, Mark L.
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experimental part
p. 91 - 97
(2010/06/14)
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- A new and efficient approach to the synthesis of nicotine and anabasine analogues
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(Chemical Equation Presented) A straightforward and practical approach was established for the synthesis of nicotine and anabasine analogues by the cyclization of mesylated 1-(3-pyridinyl)-1,4, and 1,5-diol derivatives to form the pyrrolidino or piperidino fragments. Nicotine analogue (S)-15 was prepared with good enantioselectivity using the developed azacyclization procedure of nonracemic (R)-1-pyridin-3-yl-butane-1,4-diol, which was obtained by the borane-mediated reduction of ketone 12 in the presence of the spiroborate ester derived from diphenyl prolinol and ethylene glycol.
- Huang, Kun,Ortiz-Marciales, Margarita,De Jesus, Melvin,Stepanenko, Viatcheslav
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experimental part
p. 1252 - 1258
(2010/03/23)
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- N-nitrosation of myosmine yields HPB (4-hydroxy-1-(3-pyridyl)-1- butanone) and NNN (N-nitrosonornicotine)
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N-Nitrosonornicotine (NNN) is formed by synthetic or biological N- nitrosation of the tobacco alkaloid nornicotine. Following metabolic activation of NNN, DNA and protein adducts are formed releasing 4-hydroxy-1- (3-pyridyl)-1-butanone (HPB), an actual biomarker to differentiate between tobacco smokers and passive smokers, NNN and HPB can be prepared in a new one-step reaction by N-nitrosation of the nicotinoid myosmine which has been found not only in tobacco but also in nut products. The reaction was tested also in human gastric juice. The formation rate of NNN and HPB depends on the pH value in the reaction solutions. This is important under the aspect of myosmine uptake by humans from other biological sources and subsequent biological activation. The new reaction pathway indicates that human exposure to nicotinoid nitrosation products seems to be not restricted exclusively to tobacco.
- Zwickenpflug, Wolfgang
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p. 392 - 394
(2007/10/03)
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- A novel reductive aminocyclization for the syntheses of chiral pyrrolidines: Stereoselective syntheses of (S)-nornicotine and 2-(2'-pyrrolidyl)-pyridines
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(S)-Nornicotine 2 was synthesized in four steps. A key step in the synthesis involved reductive aminocyclization of a 1,4-ketoaldehyde with 2,3,4,6-tetra-O-pivaloyl-β-D-galactosylamine 1 in the presence of sodium cyanoborohydride, diastereoselectively affording the corresponding stereoisomer 6 in 45% yield. The aminosugar moiety could be easily removed by acidic hydrolysis to furnish 2. The aminocyclization was further extended to asymmetric syntheses of novel chiral 2-(2'-pyrrolidyl)-pyridine ligands 12 and 13.
- Loh, Teck-Peng,Zhou, Jian-Rong,Li, Xu-Ran,Sim, Keng-Yeow
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p. 7847 - 7850
(2007/10/03)
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- Quinone derivatives, their production and use.
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Quinone derivatives represented by the general formula (wherein, R1 and R2, which are the same or different, refer to a hydrogen atom, methyl or methoxymethyl group, or R1 and R2 bind together to form-CH=CH-CH=CH-; R3 is a hydrogen atom or methyl group; R? is a nitrogen-containing heterocyclic group which may be substituted; R? is a hydrogen atom, methyl group, hydroxymethyl group which may be substituted, or a carboxyl group which may be (wherein, R' is a hydrogen atom or methyl group); n is an integer from 0 through 12, m is an integer from 0 through 3, and k is an integer from 0 through 7, providing that, when m is 2 or 3, Z and k are able to vary appropri-ately in the repeating unit shown in [ ] ), and the hydro-quinone derivatives thereof, are novel compounds, possess improvement effects of metabolism of poly unsaturated fatty acids, particularly two or more of inhibition of production of fatty acid peroxides, inhibition of production of metabo-lites in 5-lipoxygenase pathway, inhibition of thromboxane A? synthetase, thromboxane A? receptor antagonism and scavenging action of active oxygen species, and of use as drugs, such as antithrombotics, anti-vascular constriction agents, anti-asthma agent, antiallergic agents, therapeutics for psoriasis, agents for improvement in heart, brain and cardiovascular systems, therapeutics for nephritis, active oxygen-eliminating agents, anticancer agents, agents for improvement of control of arachidonate cascade products, etc.
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- Dual Inhibitors of Thromboxane A2 Synthase and 5-Lipoxygenase with Scavenging Activity of Active Oxygen Species. Synthesis of a Novel Series of (3-Pyridylmethyl)benzoquinone Derivatives
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A novel series of (3-pyridylmethyl)benzoquinone derivatives was molecular designed and synthesized for the dual purpose of inhibiting thromboxane A2 and leukotriene biosynthesis enzymes and scavenging active oxygen species (AOS).They were evaluated for inhibition of TXA2 synthase, inhibition of 5-lipoxygenase, and for their scavenging activity of AOS using the thiobarbituric acid method. 2,3,5-Trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (24, CV-6504) was the most promising derivative since it showed efficient AOS scavenging activity (inhibition of lipid peroxidation in rat brain homogenates: IC50 = 1.8 10-6 M) as well as potent, specific, and well-balanced inhibitory effects on both enzymes (inhibitory effect on TXA2 synthase in human blood, IC50 = 3.3 10-7 M; inhibitory effect on 5-lipoxygenase in human blood, IC50 = 3.6 10-7 M).In adriamycin-induced proteinuria in a rat model, compound 24 at 10 mg/kg per day (po) suppressed proteinuria by more than 50percent.The proteinuria, however, could not be reduced by single administration of an inhibitor specific for thromboxane A2 synthase or for 5-lipoxygenase .The proteinuria was also not reduced by administration of an AOS scavenger, 2-O-octadecylascorbic acid (4, CV-3611).Triple function compounds such as compound 24 that specifically inhibit both enzymes as well as scavenge AOS possess a variety of pharmacologically beneficial effects.
- Ohkawa, Shigenori,Terao, Shinji,Terashita, Zen-ichi,Shibouta, Yumiko,Nishikawa, Kohei
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p. 267 - 276
(2007/10/02)
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- Certain benzoquinones, naphthoquinones, corresponding hydroquinones which exhibit thromboxane A2 synthetase inhibition or receptor antagonism and the like
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Quinone derivatives represented by the general formula STR1 (wherein, R1 and R2, the same or different, refer to a hydrogen atom, methyl or methoxymethyl group, or R1 and R2 bind together to form --CH=CH--CH=CH--; R3 is a hydrogen atom or methyl group; R4 is a nitrogen-containing heterocyclic group which may be substituted; R5 is a hydrogen atom, methyl group, hydroxymethyl group which may be substituted, or a carboxyl group which may be esterified or amidated; Z is STR2 (wherein, R' is hydrogen atom or methyl group); n is an integer from 0 through 12, m is an integer from 0 through 3, and k is an integer from 0 through 7, providing that, when m is 2 or 3, Z and k are able to vary appropriately in the repeating unit shown in [ ]), and the hydroquinone derivatives thereof, are novel compounds, possess improvement effects of metabolism of polyunsaturated fatty acids, particularly two or more of inhibition of production of fatty acid peroxides, inhibition of production of metabolites in 5-lipoxygenase pathway, inhibition of thromboxane A2 synthetase, thromboxane A2 receptor antagonism and scavenging action of active oxygen species, and of use as drugs, such as antithrombotics, anti-vascular constriction agents, anti-asthma agent, antiallergic agents, therapeutics for psoriasis, agents for improvement in heart, brain and cardiovascular systems, therapeutics for nephritis, active oxygen-eliminating agents, anticancer agents, agents for improvement of control of arachidonate cascade products, etc.
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- Synthesis of Biheteroaromatic Compounds via the Isoxazoline Route
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A number of heteroaromatically substituted furans, thiophenes, pyrroles, pyridines and benzenes have been prepared via the 2-isoxazoline route.N-Acetylnornicotyrine is prepared from N-allylacetamide and 3-pyridinecarboxaldoxime.
- Ghabrial, Sami S.,Thomsen, I.,Torssell, K. B. G.
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p. 426 - 434
(2007/10/02)
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- Reactions with deoxyguanosine of 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone, a model compound for α-hydroxylation of tobacco-specific nitrosamines
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4-(3-Pyridyl)-4-oxobutanediazohydroxide (10) is a likely product of metabolic α-hydroxylation of the tobacco nitrosamines N'-nitrosonornicotine (2) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (1). The reactions of 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone (12), a stable precursor to 10, with deoxyguanosine and H2O at pH 8 were investigated. Three products of the reaction of 12 with deoxyguanosine were characterized as 2'-deoxy-N-[1-methyl-3-oxo-3-(3-pyridyl)propyl]guanosine (18), 2'-deoxyguanosine 3'-(ethyl carbonate), and 2'-deoxyguanosine 5'-(ethyl carbonate). The adduct 18 was also formed upon reaction of 1-(3-pyridyl)-2-buten-1-one (17) with deoxyguanosine. Whereas the branched chain adduct 18 was the major product formed upon reaction of 12 with deoxyguanosine, the solvolysis of 12 gave mainly the nonrearranged keto alcohol 4-hydroxy-1-(3-pyridyl)-1- butanone (21), with lesser amounts of 3-hydroxy-1-(3-pyridyl)-1-butanone (22) and 17. Possible mechanisms for the formation of 18 are discussed.
- Hecht,Lin,Chuang,Castonguay
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p. 1292 - 1295
(2007/10/02)
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