当前位置： SCI文献检索 > CHEMICAL RESEARCH IN TOXICOLOGY期刊下所有文献 > Reactive metabolite trapping screens and potential pitfalls: bioactivation of a homomorpholine and formation of an unstable thiazolidine adduct.

Reactive metabolite trapping screens and potential pitfalls: bioactivation of a homomorpholine and formation of an unstable thiazolidine adduct.

Abstract：

:Successful early attrition of potential problematic compounds is of great importance in the pharmaceutical industry. The lead compound in a recent project targeting neuropathic pain was susceptible to metabolic bioactivation, which produced reactive metabolites and showed covalent binding to protein. Therefore, as a part of the backup series for this compound several structural modifications were explored to mediate the reactive metabolite and covalent binding risk. A homomorpholine containing series of compounds was identified without compromising potency. However, when these compounds were incubated with human liver microsomes in the presence of GSH, Cys-Gly adducts were identified, instead of intact GSH conjugates. This article examines the formation of the Cys-Gly adduct with AZX ([M+H]+ 486) as a representative compound for this series. The AZX-Cys-Gly-adduct ([M+H]+ 662) showed evidence of ring contraction by formation of a thiazolidine-glycine and was additionally shown to be unstable. During its isolation for structural characterization by 1H NMR spectroscopy, it was found to have decomposed to a product with [M+H]+ 446. The characterization and identification of this labile GSH-derived adduct using LC-MS/MS and 1H NMR are described, along with observations around stability. In addition, various structurally related trapping reagents were employed in an attempt to further investigate the reaction mechanism along with a methoxylamine trapping experiment to confirm the structure of the postulated reactive intermediate.

journal_name

Chem Res Toxicol

journal_title

Chemical research in toxicology

authors

Lenz EM,Martin S,Schmidt R,Morin PE,Smith R,Weston DJ,Bayrakdarian M

doi

10.1021/tx5000409

subject

Has Abstract

pub_date

2014-06-16 00:00:00

pages

968-80

issue

6

eissn

0893-228X

issn

1520-5010

journal_volume

27

pub_type

杂志文章

相关文献

CHEMICAL RESEARCH IN TOXICOLOGY文献大全
  • Detection and characterization of a glutathione conjugate of ochratoxin A.

    abstract：:The ability of the carcinogenic mycotoxin ochratoxin A (OTA) to react with reduced glutathione (GSH) has been assessed using electrospray ionization (ES)-MS techniques. On the basis of the assumption that OTA undergoes biotransformation into the reactive quinone species OTQ (6), a synthetic sample of the reduced form ...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx0255929

    authors： Dai J,Park G,Wright MW,Adams M,Akman SA,Manderville RA

    更新日期：2002-12-01 00:00:00

  • N-Glycosylation of pig flavin-containing monooxygenase form 1: determination of the site of protein modification by mass spectrometry.

    abstract：:By using a combination of biochemical methods (i.e., endoglycosidase H digestion and immunoblot and plant lectin binding studies), it was verified that pig flavin-containing monooxygenase (FMO1) was N-glycosylated. By using mass spectrometry approaches [i.e., peptide mapping, gas chromatography/mass spectrometry, micr...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx980117p

    authors： Korsmeyer KK,Guan S,Yang ZC,Falick AM,Ziegler DM,Cashman JR

    更新日期：1998-10-01 00:00:00

  • Molecular cytotoxicity mechanisms of allyl alcohol (acrolein) in budding yeast.

    abstract：:Allyl alcohol (AA) is one of the environmental pollutants used as a herbicide and industrial chemical. AA undergoes enzymatic oxidation in vivo to form Acrolein (Acr), a highly reactive and ubiquitous environmental toxicant. The exposure to AA/Acr has detrimental effects on cells and is highly fatal. In corroboration ...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/acs.chemrestox.5b00071

    authors： Golla U,Bandi G,Tomar RS

    更新日期：2015-06-15 00:00:00

  • Epoxide ring opening and related reactivities of cyclopenta polycyclic aromatic hydrocarbons: quantum mechanical studies.

    abstract：:A series of 13 cyclopenta polycyclic aromatic hydrocarbons have been studied using quantum mechanical methods. The three-dimensional molecular structure of each carbocation that might result from the opening of a protonated epoxide ring formed between the carbon atoms completing the cyclopenta ring was computed with A...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx00026a022

    authors： Rabinowitz JR,Little SB

    更新日期：1992-03-01 00:00:00

  • Apoptotic events induced by maleimides on human acute leukemia cell lines.

    abstract：:Cyclic imides are known for their antitumor activity, especially the naphthalimide derivatives, such as Mitonafide and Amonafide. Recently, we have demonstrated the cytotoxic effect of a series of naphthalimide derivatives against B16F10 melanoma cells. On the basis of this fact, we have developed a study starting fro...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx400284r

    authors： Machado KE,de Oliveira KN,Andreossi HM,Bubniak Ldos S,de Moraes AC,Gaspar PC,Andrade Eda S,Nunes RJ,Santos-Silva MC

    更新日期：2013-12-16 00:00:00

  • In vitro model of mammary estrogen metabolism: structural and kinetic differences between catechol estrogens 2- and 4-hydroxyestradiol.

    abstract：:Estrogens and their oxidative metabolites, the catechol estrogens, have been implicated in the development of breast cancer; yet, relatively little is known about estrogen metabolism in the breast. To determine how the parent hormone, 17 beta-estradiol (E(2)), is metabolized, we used recombinant, purified phase I enzy...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx0498657

    authors： Dawling S,Hachey DL,Roodi N,Parl FF

    更新日期：2004-09-01 00:00:00

  • Studies on 4-benzyl-1-methyl-1,2,3,6-tetrahydropyridine, a nonneurotoxic analogue of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

    abstract：:Previous reports indicate that 4-benzyl-1-methyl-1,2,3,6-tetrahydropyridine (BMTP), the benzyl analogue of the Parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is not neurotoxic in the C-57 black mouse even when administered at a dose 10 times greater than the dose of MPTP required...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx00014a008

    authors： Naiman N,Rollema H,Johnson E,Castagnoli N Jr

    更新日期：1990-03-01 00:00:00

  • Excision of a lyase-resistant oxidized abasic lesion from DNA.

    abstract：:The C2'-oxidized abasic lesion (C2-AP) is produced in DNA that is subjected to oxidative stress. The lesion disrupts replication and gives rise to mutations that are dependent upon the identity of the upstream nucleotide. Ape1 incises C2-AP, but the 5'-phosphorylated fragment is not a substrate for the lyase activity ...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx9003984

    authors： Wong RS,Sczepanski JT,Greenberg MM

    更新日期：2010-04-19 00:00:00

  • Toxic metabolite formation from Troglitazone (TGZ): new insights from a DFT study.

    abstract：:The hepatotoxicity of Troglitazone (TGZ) has been ascribed to the formation of reactive metabolites, and the primary reactive metabolite of TGZ has been confirmed to be an o-quinone methide. Oxidation of the chromane moiety is also known to produce quinone containing metabolites. Quantum chemical studies have been per...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx200110h

    authors： Dixit VA,Bharatam PV

    更新日期：2011-07-18 00:00:00

  • Reactive Sulfur Species-Mediated Activation of the Keap1-Nrf2 Pathway by 1,2-Naphthoquinone through Sulfenic Acids Formation under Oxidative Stress.

    abstract：:Sulfhydration by a hydrogen sulfide anion and electrophile thiolation by reactive sulfur species (RSS) such as persulfides/polysulfides (e.g., R-S-SH/R-S-Sn-H(R)) are unique reactions in electrophilic signaling. Using 1,2-dihydroxynaphthalene-4-thioacetate (1,2-NQH2-SAc) as a precursor to 1,2-dihydroxynaphthalene-4-th...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx500416y

    authors： Shinkai Y,Abiko Y,Ida T,Miura T,Kakehashi H,Ishii I,Nishida M,Sawa T,Akaike T,Kumagai Y

    更新日期：2015-05-18 00:00:00

  • Formation, stability, and rearrangements of the glutathione conjugates of butadiene monoxide: evidence for the formation of stable sulfurane intermediates.

    abstract：:Butadiene monoxide, a toxic metabolite of 1,3-butadiene, is a substrate for the human placental glutathione (GSH) S-transferase. The products have been identified as S-(2-hydroxy-3-buten-1-yl)glutathione (I) and S-(1-hydroxy-3-buten-2-yl)glutathione (II). S-(4-hydroxy-2-buten-1-yl)glutathione (III), which was formed c...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx00022a006

    authors： Sharer JE,Duescher RJ,Elfarra AA

    更新日期：1991-07-01 00:00:00

  • The mechanism of the peroxynitrite-mediated oxidation of myoglobin in the absence and presence of carbon dioxide.

    abstract：:Among the cellular components that can react directly with peroxynitrite in the presence of physiological CO(2) concentrations are sulfur-, selenium-, and metal-containing proteins, in particular hemoproteins. We have previously shown that the reactions of peroxynitrite with oxymyoglobin (MbFeO(2)) and oxyhemoglobin p...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx025595l

    authors： Herold S,Exner M,Boccini F

    更新日期：2003-03-01 00:00:00

  • Dityrosine cross-linked Abeta peptides: fibrillar beta-structure in Abeta(1-40) is conducive to formation of dityrosine cross-links but a dityrosine cross-link in Abeta(8-14) does not induce beta-structure.

    abstract：:Recent reports by Galeazzi and co-workers demonstrated the susceptibility of Abeta(1-42) to undergo dityrosine formation via peroxidase-catalyzed tyrosine cross-linking. We have formed dityrosine cross-links in Abeta(1-40) using these enzymatic conditions as well as a copper-H(2)O(2) method. The efficiency of dityrosi...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx025666g

    authors： Yoburn JC,Tian W,Brower JO,Nowick JS,Glabe CG,Van Vranken DL

    更新日期：2003-04-01 00:00:00

  • Bioactivation of lamotrigine in vivo in rat and in vitro in human liver microsomes, hepatocytes, and epidermal keratinocytes: characterization of thioether conjugates by liquid chromatography/mass spectrometry and high field nuclear magnetic resonance spe

    abstract：:Previous studies suggested that lamotrigene (LTG) underwent bioactivation to a reactive aryl epoxide intermediate in rats. Nevertheless, definitive structures of these thioether conjugates, which are often needed to substantiate the mechanism of bioactivation and identity of reactive intermediate(s), were not fully es...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx9003243

    authors： Chen H,Grover S,Yu L,Walker G,Mutlib A

    更新日期：2010-01-01 00:00:00

  • T-Cell Activation by Low Molecular Weight Drugs and Factors That Influence Susceptibility to Drug Hypersensitivity.

    abstract：:Drug hypersensitivity reactions adversely affect treatment outcome, increase the length of patients' hospitalization, and limit the prescription options available to physicians. In addition, late stage drug attrition and the withdrawal of licensed drugs cost the pharmaceutical industry billions of dollars. This signif...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章,评审

    doi：10.1021/acs.chemrestox.9b00327

    authors： Hammond S,Thomson PJ,Ogese MO,Naisbitt DJ

    更新日期：2020-01-21 00:00:00

  • Role of cytochrome P450 enzyme induction in the metabolic activation of benzo[c]phenanthrene in human cell lines and mouse epidermis.

    abstract：:The environmental contaminant benzo[c]phenanthrene (B[c]Ph) has weak carcinogenic activity in rodent bioassays; however, the fjord region diol epoxides of B[c]Ph, B[c]Ph-3,4-diol 1,2-epoxides (B[c]PhDE), are potent carcinogens. To determine the role of cytochrome P450 isozymes in the activation of B[c]Ph in MCF-7 cell...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx960174n

    authors： Einolf HJ,Story WT,Marcus CB,Larsen MC,Jefcoate CR,Greenlee WF,Yagi H,Jerina DM,Amin S,Park SS,Gelboin HV,Baird WM

    更新日期：1997-05-01 00:00:00

  • Systematic toxicity mechanism analysis of proton pump inhibitors: an in silico study.

    abstract：:Proton pump inhibitors (PPIs) are extensively used for the treatment of gastric acid-related disorders. PPIs appear to be well tolerated and almost have no short-term side effects. However, the clinical adverse reactions of long-term PPI usage are increasingly reported in recent years. So far, there is no study that e...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx5003782

    authors： Wu D,Qiu T,Zhang Q,Kang H,Yuan S,Zhu L,Zhu R

    更新日期：2015-03-16 00:00:00

  • Identification and characterization of deoxyguanosine adducts of methyl vinyl ketone and ethyl vinyl ketone. Genotoxicity of the ketones in the SOS Chromotest.

    abstract：:The reaction of the alpha, beta-unsaturated ketones methyl vinyl ketone (MVK) and ethyl vinyl ketone (EVK) with nucleosides and 5'-mononucleotides was studied. The genotoxic activity of MVK and EVK in the SOS Chromotest was investigated. Three different types of adducts with deoxyguanosine were found and their structu...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx00019a007

    authors： Eder E,Hoffman C,Deininger C

    更新日期：1991-01-01 00:00:00

  • Enhancement of 2'-deoxyguanosine hydroxylation and DNA damage by coal and oil fly ash in relation to particulate metal content and availability.

    abstract：:Epidemiologic studies have shown causal relationships between air pollution particles and adverse health effects in susceptible subpopulations. Fly ash particles (containing water-soluble and insoluble metals) are a component of ambient air particulate pollution and may contribute to particulate-induced health effects...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx000110j

    authors： Prahalad AK,Inmon J,Ghio AJ,Gallagher JE

    更新日期：2000-10-01 00:00:00

  • Mechanism of the N-hydroxylation of primary and secondary amines by cytochrome P450.

    abstract：:Cytochrome P450 enzymes (CYPs) metabolize alkyl- and arylamines, generating several different products. For the primary and secondary amines, some of these reactions result in hydroxylated amines, which may be toxic. Thus, when designing new drugs containing amine groups, it is important to be able to predict if a giv...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx500371a

    authors： Seger ST,Rydberg P,Olsen L

    更新日期：2015-04-20 00:00:00

  • Mechanism of reaction of beta-(aryloxy)acroleins with nucleosides.

    abstract：:The mechanism of DNA adduct formation by acroleins substituted with good leaving groups in the beta-position was investigated using [3-2H]-3-(p-nitrophenoxy)acrolein (1). Reaction of 1 with guanosine at acidic pH produced 9-beta-D-ribofuranosylpyrimido[1,2-alpha]purin-10(3H)-one containing equal amounts of deuterium a...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx950105t

    authors： Reddy GR,Marnett LJ

    更新日期：1996-01-01 00:00:00

  • Titanium nanoparticle inhalation induces renal fibrosis in mice via an oxidative stress upregulated transforming growth factor-β pathway.

    abstract：:Titanium dioxide nanoparticles (Nano-TiO2) are gradually being used extensively in clinical settings, industry, and daily life. Accumulation studies showed that Nano-TiO2 exposure is able to cause injuries in various animal organs, including the lung, liver, spleen, and kidney. However, it remains unclear whether expo...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx500287f

    authors： Huang KT,Wu CT,Huang KH,Lin WC,Chen CM,Guan SS,Chiang CK,Liu SH

    更新日期：2015-03-16 00:00:00

  • Hydrolytic Cleavage Products of Globin Adducts in Urine as Possible Biomarkers of Cumulative Dose: Proof of Concept Using Styrene Oxide as a Model Adduct-Forming Compound.

    abstract：:A new experimental model was designed to study the fate of globin adducts with styrene 7,8-oxide (SO), a metabolic intermediate of styrene and a model electrophilic compound. Rat erythrocytes were incubated with SO at 7 or 22 °C. Levels of specific amino acid adducts in globin were determined by LC/MS analysis of the ...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/acs.chemrestox.5b00518

    authors： Mráz J,Hanzlíková I,Moulisová A,Dušková Š,Hejl K,Bednářová A,Dabrowská L,Linhart I

    更新日期：2016-04-18 00:00:00

  • Chemical speciation of trivalent actinides and lanthanides in biological fluids: the dominant in vitro binding form of curium(III) and europium(III) in human urine.

    abstract：:Radionuclides represent a serious health risk to humans in the case of incorporation. To elucidate the potential of time-resolved laser-induced fluorescence spectroscopy (TRLFS) to determine the dominant radionuclide species in natural biofluids, we investigated the in vitro speciation of curium(III) in human urine sa...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx100273g

    authors： Heller A,Barkleit A,Bernhard G

    更新日期：2011-02-18 00:00:00

  • Genotoxicity-related chemistry of human metabolites of benzo[ghi]perylene (B[ghi]P) investigated using electro-optical arrays and DNA/microsome biocolloid reactors with LC-MS/MS.

    abstract：:There is limited and sometimes contradictory information about the genotoxicity of the polycyclic aromatic hydrocarbon benzo[ghi]perylene (B[ghi]P). Using recently developed metabolic toxicity screening arrays and a biocolloid reactor-LC-MS/MS approach, both featuring films of DNA and human metabolic enzymes, we demon...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx400147c

    authors： Pan S,Li D,Zhao L,Schenkman JB,Rusling JF

    更新日期：2013-08-19 00:00:00

  • A comparison of the covalent binding of clozapine, procainamide, and vesnarinone to human neutrophils in vitro and rat tissues in vitro and in vivo.

    abstract：:Covalent binding of drug reactive metabolites to neutrophils or their precursors is thought to play a role in the development of drug-induced agranulocytosis. In this study, we used immunochemical techniques to compare the covalent binding of clozapine, vesnarinone, and procainamide (three drugs associated with agranu...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx050095o

    authors： Gardner I,Popović M,Zahid N,Uetrecht JP

    更新日期：2005-09-01 00:00:00

  • Hydroxyl Radicals in E-Cigarette Vapor and E-Vapor Oxidative Potentials under Different Vaping Patterns.

    abstract：:Available studies, while limited in number, suggest that e-cigarette vaping induces oxidative stress, with one potential mechanism being the direct formation of reactive oxygen species (ROS) in e-vapor. In the present studies, we measured the formation of hydroxyl radical (•OH), the most destructive ROS, in e-vapor un...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/acs.chemrestox.8b00400

    authors： Son Y,Mishin V,Laskin JD,Mainelis G,Wackowski OA,Delnevo C,Schwander S,Khlystov A,Samburova V,Meng Q

    更新日期：2019-06-17 00:00:00

  • Detection of Carbofuran-Protein Adducts in Serum of Occupationally Exposed Pesticide Factory Workers in Pakistan.

    abstract：:This study was conducted to investigate the protein adducts with pesticides in a cohort of 172 factory workers that were exposed to a mixture of pesticides. The 35 samples showing considerable variation in biochemical parameters, i.e., butyrylcholinestrase (BChE), serum glutamic pyruvic transaminase (SGPT), serum glut...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/acs.chemrestox.6b00222

    authors： Rehman T,Khan MM,Shad MA,Hussain M,Oyler BL,Goo YA,Goodlett DR

    更新日期：2016-10-17 00:00:00

  • Profiling the reactive metabolites of xenobiotics using metabolomic technologies.

    abstract：:A predominant pathway of xenobiotic-induced toxicity is initiated by bioactivation. Characterizing reactive intermediates will provide information on the structure of reactive species, thereby defining a potential bioactivation mechanism. Because most reactive metabolites are not stable, it is difficult to detect them...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx200033v

    authors： Li F,Lu J,Ma X

    更新日期：2011-05-16 00:00:00

  • Effect of intestinal glucuronidation in limiting hepatic exposure and bioactivation of raloxifene in humans and rats.

    abstract：:Raloxifene (Evista) is a second generation selective estrogen receptor modulator used in the treatment of osteoporosis and for chemoprevention of breast cancer. It is bioactivated to reactive intermediates, which covalently bind to proteins and form GSH conjugates upon incubation with NADPH and GSH-supplemented human ...

    journal_title：Chemical research in toxicology

    pub_type： 杂志文章

    doi：10.1021/tx800323w

    authors： Dalvie D,Kang P,Zientek M,Xiang C,Zhou S,Obach RS

    更新日期：2008-12-01 00:00:00