Abstract：
:The characterization of the metabolic pathways of new chemical entities with a special emphasis on detecting potentially reactive metabolites is increasingly being performed early in the drug discovery process. In the present study, the preliminary in vitro metabolic routes of a series of novel 2-substituted benzothiophene-containing discovery molecules were determined in fresh and cryopreserved hepatocyte suspensions. The objectives of this investigation were: (1) to use systematic LC/MS and LC/MS/MS analyses to provide a preliminary characterization of the in vitro metabolism of these compounds, with a particular focus on metabolites potentially arising from reactive intermediates, and (2) to identify potential lead molecules not associated with such metabolic pathways. This benzothiophene-containing series of compounds was characterized by the formation of five metabolites, at least two of which (dihydrodiol formation and glutathione adduct of the dihydrohydroxyl) were indicative of the formation of a reactive arene oxide intermediate. Tandem mass spectral analysis of the metabolites formed from a variety of structurally similar compounds demonstrated this reactive arene oxide intermediate to form on the 2-substituted benzothiophene moiety. Substitution of the benzothiophene with other functional groups eliminated these potentially toxic metabolites. The data presented here demonstrate the utility of performing metabolic route screens early in the drug discovery process prior to lengthy and costly radiolabeled studies, and furthermore, implicate a 2-substituted benzothiophene moiety as a substrate for formation of a reactive arene oxide intermediate.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Evans CA,Fries HE,Ward KWdoi
10.1016/j.cbi.2005.01.005subject
Has Abstractpub_date
2005-02-28 00:00:00pages
25-36issue
1eissn
0009-2797issn
1872-7786pii
S0009-2797(05)00020-7journal_volume
152pub_type
杂志文章abstract：:The antitumor agent cis-diamminedichloroplatinum(II) (cis-DDP) reacts covalently with DNA and disrupts its secondary structure. Damaged DNA, but not native DNA, is readily digested by S1 nuclease, an endonuclease specific for single stranded polynucleotides. We have measured S1 nuclease digestion of platinated DNA by ...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(90)90003-6
更新日期：1990-01-01 00:00:00
abstract：:In order to assess the role played respectively by the pseudothiourea group and the alkylic chain in the inhibition of protein synthesis and tumour growth caused by compound AHR-1911, a series of eight related substances were studied. The blockade of protein synthesis on liver and Walker carcinoma ribosomes and on sus...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(78)90135-7
更新日期：1978-09-01 00:00:00
abstract：:Phagocytic cells, especially neutrophils (PMNs) are specialized in the production of reactive oxygen species (ROS) to kill pathogenic agents, but an excessive ROS production is associated with tissue damages and inflammatory diseases. Phagocytes are thus prime therapeutic targets to control inflammatory events associa...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2012.12.010
更新日期：2013-01-25 00:00:00
abstract：:Tetrachlorohydroquinone (TCHQ), which has previously been identified as a metabolite of pentachlorophenol, induces DNA strand breaks in isolated DNA and in human fibroblasts. Strand break formation in PM2 DNA is prevented by the addition of catalase and the hydroxyl radical scavengers DMSO, ethanol and mannitol, where...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(90)90047-q
更新日期：1990-01-01 00:00:00
abstract：:Metabolism is a prerequisite for the development of benzene-mediated myelotoxicity. Benzene is initially metabolized via cytochromes P450 (primarily CYP2E1 in liver) to benzene-oxide, which subsequently gives rise to a number of secondary products. Benzene-oxide equilibrates spontaneously with the corresponding oxepin...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2009.12.025
更新日期：2010-03-19 00:00:00
abstract：:The enzymatic oxidation of tetrachloro-1,4-hydroquinone (1,4-TCHQ), resulting in covalent binding to protein of tetrachloro-1,4-benzoquinone (1,4-TCBQ), was investigated, with special attention to the involvement of cytochrome P-450 and reactive oxygen species. 1,4-TCBQ itself reacted very rapidly and extensively with...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(88)90110-x
更新日期：1988-01-01 00:00:00
abstract：:The mechanisms by which brassica vegetables might decrease the risk of cancer are reviewed in this paper. Brassicas, including all types of cabbages, broccoli, cauliflower and Brussels sprouts, may be protective against cancer due to their relatively high glucosinolate content. Glucosinolates are usually broken down t...
journal_title：Chemico-biological interactions
pub_type： 杂志文章,评审
doi：10.1016/s0009-2797(96)03745-3
更新日期：1997-02-28 00:00:00
abstract：:The stability of small unilamellar vesicles formed by egg phosphatidylcholine has been examined in the presence of 38 tricyclic carboxamide DNA-intercalating agents (19 phenylquinolines, 17 phenylbenzimidazoles, an acridine and an anthracene). Lysis of the vesicular membrane is time-dependent and also dependent on the...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(90)90025-i
更新日期：1990-01-01 00:00:00
abstract：:Plasma protein S-sulfonate compounds (RS-SO-3) have previously been shown to form, presumably by sulfitolysis of disulfide bonds, as a result of exposure to sulfite. In the investigations reported here, we identify two proteins in rabbit plasma, namely albumin and plasma fibronectin, which contain reactive sites for S...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(84)90052-8
更新日期：1984-04-01 00:00:00
abstract：:The organ specificity of tris(2,3-dibromopropyl)phosphate(Tris-BP)-induced DNA damage was investigated in the rat 2 h after a single i.p. injection of 350 mumol/kg. Extensive DNA damage, measured with the alkaline elution method, was found in the kidney, liver and small intestine. Less, but significant DNA damage was ...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(92)90110-7
更新日期：1992-04-15 00:00:00
abstract：:In Alzheimer's disease (AD) a reduction in acetylcholinesterase (AChE) and an increase in butyrylcholinesterase (BChE) activity are observed. K variant (539T) is the most common variant of the BCHE gene and, although controversial, several studies reported association between K variant and AD. Previous results showed ...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2012.09.008
更新日期：2013-03-25 00:00:00
abstract：:4-Trifluoromethylphenol (4-TFMP) was cytotoxic to precision-cut rat liver slices as indicated by loss of intracellular potassium. Intracellular glutathione levels decreased and fluoride ion levels increased in a time and concentration-dependent manner. The cytotoxicity of 4-TFMP did not appear to be due to the release...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(99)00162-3
更新日期：2000-04-14 00:00:00
abstract：:Dehydrogenase/reductase (SDR family) member 7 (DHRS7, retSDR4, SDR34C1) is a previously uncharacterized member of the short-chain dehydrogenase/reductase (SDR) superfamily. While human SDR members are known to play an important role in various (patho)biochemical pathways including intermediary metabolism and biotransf...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2013.11.003
更新日期：2014-01-25 00:00:00
abstract：:Misonidazole is readily reduced by zinc dust in aqueous solution in the presence of ammonium chloride. High pressure liquid chromatographic (HPLC) separation of the reduction mixture revealed the presence of three products. These were identified as the hydroxylamine, amine and the hydrazo derivative of misonidazole. T...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(81)90016-8
更新日期：1981-08-01 00:00:00
abstract：:An updated biokinetic model for human exposures to cobalt (Co) was developed based on a comprehensive set of human pharmacokinetics data collected from five male and five female volunteers who ingested ∼1 mg Co/day of a Co supplement for 3 months. Three key experimental observations from the human dosing studies were ...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2014.04.001
更新日期：2014-06-05 00:00:00
abstract：:Treatment of rats with the aminonucleoside of puromycin, which increases the incorporation of labelled phenylalanyl-tRNA into polypeptide chains in liver ribosome preparations studied in vitro, did not change the factor-dependent binding of fMet-tRNA f Met to ribosomes nor the peptidyl transferase function of the ribo...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(75)90010-1
更新日期：1975-11-01 00:00:00
abstract：:Ethanol abuse is a serious public health problem that is associated with several stages of alcoholic liver disease (ALD) and a high incidence of morbidity and mortality. Alcoholic fatty liver disease (AFLD), the earliest stage of ALD, is a multifactorial injury that involves oxidative stress and disruptions of lipid m...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2016.10.003
更新日期：2016-12-25 00:00:00
abstract：:It has been detected that hepatic adenosine A(2A) receptors play an active role in the pathogenesis of hepatic fibrosis and suggest a novel therapeutic target in the treatment and prevention of hepatic cirrhosis. In this paper we examined if our new triazine derivative (IMT) can inhibit ethanol-induced activation of H...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2011.10.004
更新日期：2012-01-05 00:00:00
abstract：:In the present study, a new series of 2-amino-pyran-3-carbonitrile derivatives of curcumin 2-7 have been synthesized via one-pot simple and efficient protocol, involving the reaction of curcumin 1 with substituted-benzylidene-malononitrile to modify the 1,3-diketone moiety. The structures of the synthesized compounds ...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2016.11.010
更新日期：2016-12-25 00:00:00
abstract：:Tamoxifen, widely used as adjuvant therapy in the treatment of breast cancer, is now undergoing trials as a cancer chemopreventative agent. Previous work has shown an association between 32P-postlabelled adducts in rat liver DNA and the development of liver tumours. With the use of accelerator mass spectrometry, [14C]...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(97)00063-x
更新日期：1997-09-12 00:00:00
abstract：:Passive paracellular absorption, regulated by tight junctions (TJs), is the main route for absorption of poorly absorbed hydrophilic substances. Surface active substances, such as fatty acids, may enhance absorption of these substances by affecting the integrity of TJ and increasing the permeability. It has been sugge...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2009.06.016
更新日期：2009-10-07 00:00:00
abstract：:By rapid hydrolysis of the neurotransmitter, acetylcholine, acetylcholinesterase terminates neurotransmission at cholinergic synapses. Acetylcholinesterase is a very fast enzyme, functioning at a rate approaching that of a diffusion-controlled reaction. The powerful toxicity of organophosphate poisons is attributed pr...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2010.01.042
更新日期：2010-09-06 00:00:00
abstract：:It is known that procymidone modifies sexual differentiation in vivo and in vitro, and that it induces vitellogenin (Vtg) synthesis in primary cultured rainbow trout hepatocytes. The aim of this study was to evaluate the mechanism underlying this latter in vitro estrogenic action. The cells were treated for 24 h with ...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2003.12.006
更新日期：2004-03-15 00:00:00
abstract：:Nephrotoxicity is a major adverse effect of chromium poisoning. In the present study, we investigated the potential renoprotective effect and underlying mechanisms of carvedilol, a non-specific β-adrenergic blocker using rat model of potassium dichromate-induced nephrotoxicity. Rats were pretreated with carvedilol (10...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2014.09.009
更新日期：2014-11-05 00:00:00
abstract：:Sulfation and sulfate conjugate hydrolysis play an important role in metabolism, and are catalysed by members of the sulfotransferase and sulfatase enzyme super-families. In general, sulfation is a deactivating, detoxication pathway, but for some chemicals the sulfate conjugates are much more reactive than the parent ...
journal_title：Chemico-biological interactions
pub_type： 杂志文章,评审
doi：10.1016/s0009-2797(97)00117-8
更新日期：1998-02-20 00:00:00
abstract：:The reactive oxygen species (ROS) induced oxidative stress is an inevitable factor for the pathogenesis of cardiovascular diseases. The edible marine algae-derived sulfated polysaccharides gained special attention as novel bioactive compounds having potential pharmacological activities. The present study evaluated in ...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2019.05.044
更新日期：2019-08-01 00:00:00
abstract：:S-(2,5-Dihydroxyphenyl)-cysteine and S-(2,5-dihydroxyphenyl)-N-acetyl-cysteine [the cysteine- and N-acetyl-cysteine adducts, respectively, of hydroquinone (HQ)] were identified and quantified in the urine of mice administered [ring-U-14C]acetaminophen [14C]APAP, 200 mg kg-1, i.p.). Urine was collected for 24 h and fra...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(88)90008-7
更新日期：1988-01-01 00:00:00
abstract：:Aromatic amines are important intermediates in industrial manufacturing. N-oxidation to the N-hydroxyarylamines is a key step determining the genotoxic properties of aromatic amines. N-hydroxyarylamines can form adducts with DNA, with tissue proteins and with the blood proteins albumin and hemoglobin in a dose-depende...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(92)90029-k
更新日期：1992-01-01 00:00:00
abstract：:The mechanisms by which soybean- and soybean isoflavone-enriched diets inhibit carcinogenesis are not known. We found that the isoflavones genistin and daidzin, and their respective aglucone forms daidzein and genistein, block 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin)-induced CYP1A1 enzyme activity. This inhi...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(99)00121-0
更新日期：1999-11-15 00:00:00
abstract：:Several species of columnar cacti in the Sonoran Desert contain isoquinoline alkaloids that are toxic to all but the resident drosophilids that feed and breed in necrotic stems. Cytochrome P450 enzymes are known to be involved in the metabolic detoxification of these alkaloids by the desert Drosophila and are conseque...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(99)00161-1
更新日期：2000-03-01 00:00:00
