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Activity-based protein profiling reveals broad reactivity of the nerve agent sarin

TNO Defensie en Veiligheid (author), Tuin, A.W. (author), Mol, M.A.E. (author), van den Berg, R.M. (author), Fidder, A. (author), van der Marel, G.A. (author), Overkleeft, H.S. (author), Noort, D. (author)

Elucidation of noncholinesterase protein targets of organophosphates, and nerve agents in particular, may reveal additional mechanisms for their high toxicity as well as clues for novel therapeutic approaches toward intoxications with these agents. Within this framework, we here describe the synthesis of the activity-based probe 3, which...

article 2009

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Retrospective detection of sulfur mustard exposure by mass spectrometric analysis of adducts to albumin and hemoglobin: An in vivo study

Noort, D. (author), Fidder, A. (author), Degenhardt-Langelaan, C.E.A.M. (author), Hulst, A.G. (author), TNO Defensie en Veiligheid (author)

The persistence in rats of sulfur mustard adducts to albumin and hemoglobin was studied in vivo after exposure (intravenously; 0.3 mg/kg; approximately 0.1 LD50) of rats to sulfur mustard. The albumin adduct (S-HETE)Cys-Pro-Tyr was detectable up to 7 days after the exposure, while the adduct to the N-terminal valine in hemoglobin was still...

article 2008

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Alkylphospholipids inhibit capillary-like endothelial tube formation in vitro: Antiangiogenic properties of a new class of antitumor agents

Zerp, S.F. (author), Vink, S.R. (author), Ruiter, G.A. (author), Koolwijk, P. (author), Peters, E. (author), van der Luit, A.H. (author), de Jong, D. (author), Budde, M. (author), Bartelink, H. (author), van Blitterswijk, W.J. (author), Verheij, M. (author), TNO Kwaliteit van Leven (author)

Synthetic alkylphospholipids (APLs), such as edelfosine, miltefosine and perifosine, constitute a new class of antineoplastic compounds with various clinical applications. Here we have evaluated the antiangiogenic properties of APLs. The sensitivity of three types of vascular endothelial cells (ECs) (bovine aortic ECs, human umbilical vein ECs...

article 2008

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Reversible denaturation of Brazil nut 2S albumin (Ber e1) and implication of structural destabilization on digestion by pepsin

Koppelman, S.J. (author), Nieuwenhuizen, W.F. (author), Gaspari, M. (author), Knippels, L.M.J. (author), Penninks, A.H. (author), Knol, E.F. (author), Hefle, S.L. (author), de Jongh, H.H.J. (author), TNO Kwaliteit van Leven (author)

The high resistance of Brazil nut 2S albumin, previously identified as an allergen, against proteolysis by pepsin was examined in this work. Although the denaturation temperature of this protein exceeds the 110 °C at neutral pH, at low pH a fully reversible thermal denaturation was observed at ∼82 °C. The poor digestibility of the protein by...

article 2005

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Carbazole compounds as host materials for triplet emitters in organic light-emitting diodes: Polymer hosts for high-efficiency light-emitting diodes

van Dijken, A. (author), Bastiaansen, J.J.A.M. (author), Kiggen, N.M.M. (author), Langeveld, B.M.W. (author), Rothe, C. (author), Monkman, A. (author), Bach, I. (author), Stössel, P. (author), Brunner, K. (author), TNO Industrie (author)

A carbazole homopolymer and carbazole copolymers based on 9,9′-dialkyl-[3,3′]-bicarbazolyl, 2,5-diphenyl-[1,3,4]-oxadiazole and 9,9-bis(4-[3,7-dimethyloctyloxy]phenyl)fluorene were synthesized and their electrical and photophysical properties were characterized with respect to their application as host in phosphorescent polymer light-emitting...

article 2004

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Retrospective detection of exposure to sulfur mustard: Improvements on an assay for liquid chromatography-tandem mass spectrometry analysis of albumin/sulfur mustard adducts

Prins Maurits Laboratorium TNO (author), Noort, D. (author), Fidder, A. (author), Hulst, A.G. (author), Woolfitt, A.R. (author), Ash, D. (author), Barr, J.R. (author)

We here report on the further development of the method comprising the pronase digestion of albumin alkylated by sulfur mustard and the subsequent mass spectrometric analysis of an adducted tripeptide. This includes significant improvements in both the albumin isolation procedure and the automation of the microliquid chromatography-electrospray...

article 2004

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Design, synthesis, and evaluation of sugar amino acid based inhibitors of protein prenyl transferases PFT and PGGT-1

TNO Preventie en Gezondheid (author), El Oualid, F. (author), Burm, B.E.A. (author), Leroy, I.M. (author), Cohen, L.H. (author), van Boom, J.H. (author), van den Elst, H. (author), Overkleeft, H.S. (author), van der Marel, G.A. (author), Overhand, M. (author)

Eleven analogues of the C-terminal Ca1a2X motif found in natural substrates of the prenyl transferases PFT and PGGT-1 were synthesized and evaluated for their inhibition potency and selectivity against PFT and PGGT-1. Replacement of the central dipeptide part a1a 2 by a benzylated sugar amino acid resulted in a good and highly selective PFT...

article 2004

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Melphalan antitumor efficacy and hepatotoxicity: The effect of variable infusion duration in the hepatic artery

Rothbarth, J. (author), Woutersen, R.A. (author), Sparidans, R.W. (author), van de Velde, C.J.H. (author), Mulder, G.J. (author)

The optimum conditions (duration and concentration) of a fixed dose, intra-arterial melphalan infusion in relation to its antitumor effect and toxicity in the liver were investigated in a rat colon tumor model (CC531) of liver metastases. We studied the difference in tumor and liver uptake, as well as antitumor effect and hepatotoxicity after 5-...

article 2003

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Modification of human serum albumin by acrylamide at cysteine-34: A basis for a rapid biomonitoring procedure (Letter to the editor)

Noort, D. (author), Fidder, A. (author), Hulst, A.G. (author), Prins Maurits Laboratorium TNO (author)

article 2003

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Determination of alkylphosphonic acids by microcolumn liquid chromatography with gradient elution coupled on-line with flame photometric detection

Hooijschuur, E.W.J. (author), Kientz, C.E. (author), Brinkman, U.A.T. (author)

Microcolumn liquid chromatography with gradient elution and on-line flame photometric detection has been used for the selective and rapid determination of non-volatile alkylphosphonic acids, which are hydrolysis products of nerve agents, in aqueous samples. A make-up of water was used to maintain stable introduction of the eluent during a...

article 2001

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Alkylation of human serum albumin by sulfur mustard in vitro and in vivo: Mass spectrometric analysis of a cysteine adduct as a sensitive biomarker of exposure

Noort, D. (author), Hulst, A.G. (author), de Jong, L.P.A. (author), Benschop, H.P. (author)

To develop a mass spectrometric assay for the detection of sulfur mustard adducts with human serum albumin, the following steps were performed: quantitation of the binding of the agent to the protein by using [14C] sulfur mustard and analysis of acidic and tryptic digests of albumin from blood after exposure to sulfur mustard for identification...

article 1999

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Exploring the active center of human acetylcholinesterase with stereomers of an organophosphorus inhibitor with two chiral centers

Ordentlich, A. (author), Barak, D. (author), Kronman, C. (author), Benschop, H.P. (author), de Jong, L.P.A. (author), Ariel, N. (author), Barak, R. (author), Segall, Y. (author), Velan, B. (author), Shafferman, A. (author)

The stereoselectivity of the phosphonylation reaction and the effects of adduct configuration on the aging process were examined for human acetylcholinesterase (HuAChE) and its selected active center mutants, using the four stereomers of 1,2,2-trimethylpropyl methylphosphonofluoridate (soman). The reactivity of wild type HuAChE toward the P(S)...

article 1999

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Synthesis of reduced collagen crosslinks

van den Nieuwendijk, A.M.C.H. (author), Benningshof, J.C.J. (author), Wegmann, V. (author), Bank, R.A. (author), te Koppele, J.M. (author), Brussee, J. (author), van der Gen, A. (author), TNO Preventie en Gezondheid (author)

A new synthetic route to reduced collagen crosslinks (LNL and HLNL) is described in this report. It enables an enantioselective synthesis of LNL. HLNL was obtained as a mixture of two diastereoisomers. This method also provides the possibility to introduce radio-labels during the synthesis.

article 1999

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The ecotoxicity and the biodegradability of lactic acid, alkyl lactate esters and lactate salts

Bowmer, C.T. (author), Hooftman, R.N. (author), Hanstveit, A.O. (author), Venderbosch, P.W.M. (author), van der Hoeven, N. (author), Centraal Instituut voor Voedingsonderzoek TNO TNO Voeding (author)

The ecotoxicity of lactic acid, its alkyl esters and selected metal salts was studied experimentally with the micro alga Selenastrum capricornutum, the crustacean Daphnia magna and the fish species Brachydanio rerio and Pimephales promelas. In addition, the biodegradation of lactate esters was also studied. The aim of the study was to provide...

article 1998

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Identification of the C3H7 moiety of isopropyl- and propylphosphonates by electrospray tandem mass spectrometry

van Baar, B.L.M. (author), Hulst, A.G. (author), Wils, E.R.J. (author), Prins Maurits Laboratorium TNO (author)

Structure analysis of phosphorus compounds within the framework of the Chemical Weapons Convention requires the specific identification of alkyl substituents on phosphorus. In this work the distinction of the P-propyl substituent in propylphosphonic acid derivatives by electrospray tandem mass spectrometry was investigated. P-Isopropyl and P-n...

article 1998

document

Cross-linking of starch with bifunctional precursors of nitroalkenes

Heeres, A. (author), van Doren, H.A. (author), Gotlieb, K.F. (author), Bleeker, I.P. (author), Kellogg, R.M. (author), Centraal Instituut voor Voedingsonderzoek TNO (author)

Granular starch was cross-linked with 1,3-di-O-acetyl-2-nitro-1,3-propanediol (1), 1,3-di-O-pivaloyl-2-nitro-1,3-propanediol (2), 2-nitro-3-O-pivaloyl-1-propene-3-ol (3), 1,3-di-O-acetyl-aci-2-nitro-1,3-propanediol (4), 1,3-di-O-pivaloyl-aci-2-nitro-1,3-propanediol (5) and 1,6-di-O-acetyl-2,5-dinitro-1,6-hexanediol (6). The bifunctional...

article 1998

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DNA adducts, mutant frequencies, and mutation spectra in various organs of λlacZ mice exposed to ethylating agents

Mientjes, E.J. (author), Luiten-Schuite, A. (author), van der Wolf, E. (author), Borsboom, Y. (author), Bergmans, A. (author), Berends, F. (author), Lohman, P.H.M. (author), Baan, R.A. (author), van Delft, J.H.M. (author), Centraal Instituut voor Voedingsonderzoek TNO (author)

To investigate tissue-specific relations between DNA adducts and mutagenesis in vivo, λlacZ transgenic mice were treated i.p. with N-ethyl-N-nitrosourea (ENU), diethylnitrosamine (DEN), and ethyl methanesulphonate (EMS). In liver, bone marrow, and brain DNA from mice sacrificed at several time points after treatment O6-ethylguanine (O6-EtG) and...

article 1998

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Gene-mutation assays in lambda-lacZ transgenic mice: Comparison of lacZ with endogenous genes in splenocytes and small intestinal epithelium

van Delft, J.H.M. (author), Bergmans, A. (author), van Dam, F.J. (author), Tates, A.D. (author), Howard, L. (author), Winton, D.J. (author), Baan, R.A. (author)

Comparison of results derived from transgenic animal gene-mutation assays with those from mutation analyses in endogenous genes is an important step in the validation of the former. We have used λlacZ transgenic mice to study alkylation-induced mutagenesis in vivo in (a) lacZ and hprt in spleen cells, and (b) lacZ and Dlb-1 in small intestine...

article 1998

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Trace element concentrations and stable lead isotopes in soils as tracers of lead pollution in Graft-De Rijp, the Netherlands

Walraven, N. (author), van Os, B.J.H. (author), Klaver, G.Th. (author), Baker, J.H. (author), Vriend, S.P. (author), Rijks Geologische Dienst (author)

Graft-De Rijp is a former village of whalers, situated twenty-five kilometres north of Amsterdam, the Netherlands. Since the foundation of De Rijp in 1612 a mixture of sludge, manure and town refuse (containing Pb-based household artefacts and Pb-based building materials) was used to raise and fertilise the land. Gasworks, coal storehouses,...

article 1997

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Direct determination of the chemical composition of acetylcholinesterase phosphonylation products utilizing electrospray-ionization mass spectrometry

Barak, R. (author), Ordentlich, A. (author), Barak, D. (author), Fischer, M. (author), Benschop, H.P. (author), de Jong, L.P.A. (author), Segall, Y. (author), Velan, B. (author), Shafferman, A. (author)

While non-reactivability of cholinesterase from their phosphyl conjugates (aging) is attributed to an unimolecular process involving loss of alkyl group from the phosphyl moiety, no conclusive evidence is available that this is the only reaction path and involvement of other post-inhibitory processes cannot be ruled out, To address this issue,...

article 1997