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  • 1
    Keywords: IN-VIVO ; LUNG-CANCER ; SYSTEM ; TISSUE ; DNA ; CARCINOGENESIS ; DIESEL EXHAUST ; AIR-POLLUTION ; RAT ; CONTAMINANT 3-NITROBENZANTHRONE ; RATS ; LINKAGE ; IDENTIFICATION ; genotoxicity ; HUMAN ACETYLTRANSFERASES ; METABOLIC-ACTIVATION ; POLLUTANT 3-NITROBENZANTHRONE ; Jun ; ADDUCTS ; rodent ; STANDARD ; V79 CELLS ; RE ; ADDUCT ; MUTAGEN 3-NITROBENZANTHRONE ; SULFOTRANSFERASES ; DNA ADDUCT
    Abstract: 3-Nitrobenzanthrone (3-NBA) is a potent mutagen and potential human carcinogen identified in diesel exhaust and ambient air particulate matter. 3-NBA forms DNA adducts in rodent tissues that arise principally through reduction to N-hydroxy-3-aminobenzanthrone (N-OHABA), esterification to its acetate or sulfate ester, and reaction of this activated ester with DNA. We detected 3-NBA-derived DNA adducts in rodent tissues by P-32-postlabeling and generated them chemically by acid-catalyzed reaction of N-OH-ABA with DNA, but their structural identification has not yet been reported. We have now prepared 3-NBA-derived adducts by reaction of a possible reactive metabolite, N-acetoxy-N-acetyl-3-aminobenzanthrone (N-Aco-N-Ac-ABA), with purine nucleosides and nucleotides, characterized them, and have shown that they are present in DNA treated with this 3-NBA derivative. Three of these adducts have been characterized as the C-C adduct N-acetyl-3-amino-2-(2'-deoxyguanosin-8-yl)benzanthrone, the C-N adduct N-acetyl-N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone, and an unusual 3-acetylaminobenzanthrone adduct of deoxyadenosine, which involves a double linkage between adenine and benzanthrone (N1 to C1, N6 to C11b), creating a five-membered imidazo type ring system. According to IUPAC fused ring conventions, we propose the following systematic name for this adduct: (9'-(2"-deoxyribofuranosyl))purino[6',1':2,3]imidazo[5,4-p]-(1,11b-dihyd ro-(N-acetyl-3-amino))benzanthrone. The X-phosphates of these novel adducts could be 5'-postlabeled using [gamma-P-32]ATP, although the efficiency of labeling was found to be low (less than 20%). However, none of these adducts could be detected in DNA from 3-NBA-treated rats by P-32-postlabeling. Two of these synthetic adducts were treated with alkali to generate nonacetylated adducts, and these were also shown by HPLC to differ from those adducts found in rat DNA. Therefore, a different approach to the synthesis of authentic standards is needed for the structural characterization of 3-NBA-derived DNA adducts formed in vivo
    Type of Publication: Journal article published
    PubMed ID: 15962941
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  • 2
  • 3
    Keywords: CANCER ; Germany ; human ; KINASE ; DNA adducts ; DNA ; CONTRAST ; SPECTROSCOPY ; FORM ; IDENTIFICATION ; IN-SITU ; ASSAY ; NMR ; BLADDER ; URINARY-BLADDER ; NUCLEOTIDES ; ATP ; Jun ; ADDUCTS ; P-32 POSTLABELING ANALYSIS ; MASSES ; STANDARD ; AGENT ; DNA-ADDUCTS ; thymus ; CARCINOGEN ; STANDARDS ; EXTRACTION ; 4-AMINOBIPHENYL-DNA ADDUCTS ; ALKYL SUBSTITUENTS ; CARCINOGEN-DNA ADDUCTS ; HUMAN UROEPITHELIAL CELLS ; MUTAGENIC AROMATIC-AMINES ; TOBACCO-SMOKE
    Abstract: The (32)p-postlabeling assay is an extremely sensitive technique for detecting carcinogen-DNA adducts. However, for the assignment of DNA adduct structures and the accurate determination of DNA adduct levels by (32)p-postlabeling, authentic adduct standards are needed. For Most P-32-postlabeling applications, such verified synthetic standard compounds are required in the form of their deoxynucleoside X-phosphates because they represent substrates for the polynucleotide kinase for transfer of [(32)p] phosphate from [gamma-P-32] ATP. Three N-(deoxyguanosin)4-aminobiphenyl X-phosphate adducts were prepared and fully characterized by H-1 NMR and mass spectroscopy to serve as standards for the 32P-postlabeling assay. Apart from the C8-and the N-2-deoxyguanosine X-phosphate adducts of the mutagenic human bladder carcinogen 4-aminobiphenyl (dG3'p-C8-4-ABP and dG3'p-N2-4-ABP), the C8-deoxyguanosine X-phosphate adduct of the nonmitagenic 4'-tert-butyl-4-aminobiphenyl (dG3'p-C8-4'tBu-4-ABP) was included in the study. Both C8-deoxyguanosine X-phosphate adducts were prepared by the in situ formation of deoxyguanosine X-phosphate and its subsequent reaction with the appropriate electrophilic amination agent (N-acetoxy compound). The N2-deoxyguanosine X-phosphate adduct was obtained by a modification of a previously described procedure for the synthesis of N2-deoxyguanosine adducts of aromatic amines. The three adduct standards were added at different concentrations to calf thymus DNA, and adduct recoveries were determined by the 32p-postlabeling assay under conditions routinely used in the standard methodology, enhancement by nuclease P1 digestion and enhancement by butanol extraction. The dG3'p-C8-4-ABP adduct was recovered irrespective of the concentration with approximately 30% in both the standard and the butanol extraction version of the assay. Both C8-deoxyguanosine X-phosphate adducts were sensitive to nuclease P1 digestion resulting in recoveries of only 1-3%. In contrast, the dG3'p-N2-4-ABP adduct was resistant to nuclease P1 digestion; however, recovery in all three versions was poor (1-2%) resulting in a detection limit of one adduct/10(6) nucleotides. These results demonstrate that the P-32-postlabeling assay underestimates the level of DNA adducts formed by 4-ABP and indicates that there is a need to determine the recovery for each adduct to be analyzed by the P-32-postlabeling technique
    Type of Publication: Journal article published
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  • 4
    Keywords: SIMULATIONS ; CELLS ; Germany ; MODEL ; liver ; PROTEINS ; LINES ; tumour ; DYNAMICS ; SIMULATION ; BINDING ; CELL-LINES ; fibroblasts ; MOUSE ; PATTERNS ; LINE ; MELANOMA ; ADHESION ; MIGRATION ; LENGTH ; cell lines ; carbohydrates ; ANIMAL LECTINS ; molecular ; extracellular matrix ; cell adhesion ; glycobiology ; ALPHA-5-BETA-1 INTEGRIN RECEPTOR ; B-16 MELANOMA VARIANTS ; biomimetic synthesis ; cell-surface lectins ; GALECTINS ; MEDIATED ADHESION ; molecular modeling
    Abstract: With the aim of establishing a versatile and easy synthesis of branched saccharides for biological applications, we used molecular-dynamics simulations to model Lewis(y) to two classes of dilor triantennary saccharide mimetics. One set of, mimetics was based on 1,3,5-tris(hydroxymethyl)cyclohexane (TMC) as the core, the other on furan, and both were derivatised with galactose and/or fucose. The TMC-based saccbarides were biotinylated, while the furan disaccharides were treated with maleimide-activated biotin in a Diels-Alder fashion to yield oxazatricyclodecanes (OTDs). These were then assayed as cell-surface labels in human colon (SW480 and CaCo-2), liver (PLC), Glia (U333 CG 343) and ovary (SKOV-3) tumour cell lines. Discrete staining patterns were observed in all cells, usually at one or two poles of the cells, particularly with the asymmetric 3-beta-(L)-fucopyranosyloxymethyl-4-beta-(D)-galactopyranosyloxymethyl-O TD. Normal SV40-transformed fibroblasts (SV80) showed no staining. Adhesion of the highly metastatic mouse melanoma fine B16F10 to fibronectin was inhibited by 80% by the TMC-digalactoside and by 30% by 3,4-bis(beta-(D)-galactopyranosyloxymethyl)furan. None of the saccharide mimetics inhibited the adhesion of the less metastatic B16F1 line. Migration of B16F10 cells through Matrigel(TM) was greatly inhibited by the TMC-digalactoside and weakly inhibited by the TMC-trigalactoside. The saccharide mimetics that had shown the best structural agreements with the terminal saccharides of Lewis(y) in the molecular dynamics simulation were also the most biologically potent compounds; this underlines the predictive nature of molecular dynamics simulations. The use of the nonsaccharide cores enabled us to adopt spacer lengths and terminal saccharides to optimise the structures to bind more avidly to cell-surface lectins
    Type of Publication: Journal article published
    PubMed ID: 15651048
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  • 5
    Keywords: CELLS ; Germany ; THERAPY ; imaging ; SYSTEM ; TOOL ; GENOME ; DRUG ; MOLECULES ; DNA ; INTERVENTION ; molecular imaging ; RECOGNITION ; ACID ; PEPTIDE NUCLEIC-ACIDS ; TARGET ; REQUIRES ; DERIVATIVES ; DELIVERY ; STABILITY ; diagnostics ; sensitivity ; specificity ; FUTURE ; GENE DELIVERY ; CHEMISTRY ; OLIGONUCLEOTIDE ; development ; SUBSTRATE ; PERSPECTIVES ; DRUGS ; ANALOGS ; THYMINE ; antisense ; CLICK CHEMISTRY ; INTERVENTIONS ; LIGATION ; MODALITY ; Nucleic acids ; Click-Chemistry ; CELLULAR DELIVERY ; Diels Alder Reaction(invers) (DAR(inv)) ; Peptide Nucleic Acid (PNA) ; PNA building block functionalization
    Abstract: Progress in genome research led to new perspectives in diagnostic applications and to new promising therapies. On account of their specificity and sensitivity, nucleic acids (DNA/RNA) increasingly are in the focus of the scientific interest. While nucleic acids were a target of therapeutic interventions up to now, they could serve as excellent tools in the future, being highly sequence-specific in molecular diagnostics. Examples for imaging modalities are the representation of metabolic processes (Molecular Imaging) and customized therapeutic approaches ("Targeted Therapy"). In the individualized medicine nucleic acids could play a key role; this requires new properties of the nucleic acids, such as stability. Due to evolutionary reasons natural nucleic acids are substrates for nucleases and therefore suitable only to a limited extent as a drug. To use DNA as an excellent drug, modifications are required leading e.g. to a peptide nucleic acid (PNA). Here we show that an easy substitution of nucleobases by functional molecules with different reactivity like the Reppe anhydride and pentenoic acid derivatives is feasible. These derivatives allow an independent multi-ligation of functionalized compounds, e.g. pharmacologically active ones together with imaging components, leading to local concentrations sufficient for therapy and diagnostics at the same time. The high chemical stability and ease of synthesis could enhance nucleic chemistry applications and qualify PNA as a favourite for delivery. This system is not restricted to medicament material, but appropriate for the development of new and highly efficient drugs for a sustainable pharmacy
    Type of Publication: Journal article published
    PubMed ID: 20617125
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  • 6
    Keywords: KINASE ; GENE-EXPRESSION ; TRANSCRIPTION FACTOR ; CYCLOSPORINE-A ; SIGNAL-TRANSDUCTION ; KAPPA-B ACTIVATION ; CYTOKINE PRODUCTION ; CHANNELS ; CHEMOPREVENTIVE AGENT ; LYMPHOCYTE-PROLIFERATION
    Abstract: Curcumin is the active ingredient of the spice turmeric and has been shown to have a number of pharmacologic and therapeutic activities including antioxidant, anti-microbial, anti-inflammatory, and anti-carcinogenic properties. The anti-inflammatory effects of curcumin have primarily been attributed to its inhibitory effect on NF-kappaB activity due to redox regulation. In this study, we show that curcumin is an immunosuppressive phytochemical that blocks T cell-activation-induced Ca(2+) mobilization with IC(50) = approximately 12.5 muM and thereby prevents NFAT activation and NFAT-regulated cytokine expression. This finding provides a new mechanism for curcumin-mediated anti-inflammatory and immunosuppressive function. We also show that curcumin can synergize with CsA to enhance immunosuppressive activity because of different inhibitory mechanisms. Furthermore, because Ca(2+) is also the secondary messenger crucial for the TCR-induced NF-kappaB signaling pathway, our finding also provides another mechanism by which curcumin suppresses NF-kappaB activation.
    Type of Publication: Journal article published
    PubMed ID: 22303019
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  • 7
    Keywords: CELLS ; Germany ; LIMITATION ; YEAST ; HEAT-SHOCK ; STRESS ; GLYCOGEN ; FLUORESCENCE ; CEREVISIAE ; WORKING YEASTS ; yeast,flow cytometry,trehalose,stress factors
    Type of Publication: Journal article published
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  • 8
    Keywords: CELLS ; COMBINATION ; Germany ; THERAPY ; SYSTEM ; SYSTEMS ; PROTEINS ; MOLECULES ; TARGET ; PEPTIDES ; diagnostics ; CHEMISTRY ; TRANSPORTER ; ELECTRON-DENSITY ; temozolomide ; DRUGS ; 1,2,4,5-TETRAZINES ; Adaptor Systems ; AZIDES ; BIOCONJUGATION ; Click-Chemistry ; CYCLOADDITION ; DIENE-MODIFIED OLIGONUCLEOTIDES ; DIMETHYL 1,2,4,5-TETRAZINE-3,6-DICARBOXYLATE ; inverse Diels Alder Reaction ; Ligation chemistry ; Linker Systems ; STAUDINGER LIGATION ; TERMINAL ALKYNES ; Tetrazines ; TMZ-BioShuttle ; Triazines
    Abstract: The ligation of active pharmaceutical ingredients (API) for working with image processing systems in diagnostics (MRT) attracts increasing notice and scientific interest. The Diels-Alder ligation Reaction with inverse electron demand (DAR(inv)) turns out to be an appropriate candidate. The DAR(inv) is characterized by a specific distribution of electrons of the diene and the corresponding dienophile counterpart. Whereas the reactants in the classical Diels-Alder Reaction feature electron-rich diene and electron-poor dienophile compounds, the DAR(inv) exhibits exactly the opposite distribution of electrons. Substituents with pushing electrones increase and, with pulling electrons reduce the electron density of the dienes as used in the DAR(inv). We report here that the DAR(inv) is an efficient route for coupling of multifunctional molecules like active peptides, re-formulated drugs or small molecules like the alkyalting agent temozolomide (TMZ). This is an example of our contribution to the "Click chemistry" technology. In this case TMZ is ligated by DAR(inv) as a cargo to transporter molecules facilitating the passage across the cell membranes into cells and subsequently into subcellular components like the cell nucleus by using address molecules. With such constructs we achieved high local concentrations at the desired target site of pharmacological action. The DAR(inv) ligation was carried out using the combination of several technologies, namely: the organic chemistry and the solid phase peptide synthesis which can produce 'tailored' solutions for questions not solely restricted to the medical diagnostics or therapy, but also result in functionalizations of various surfaces qualified amongst others also for array development. We like to acquaint you with the DAR(inv) and we like to exemplify that all ligation products were generated after a rapid and complete reaction in organic solutions at room temperature, in high purity, but also, hurdles and difficulties on the way to the TMZ-BioShuttle conjugate should be mentioned. With this report we would like to stimulate scientists working with the focus on "Click chemistry" to intensify research with this expanding DAR(inv) able to open the door for new solutions inconceivable so far
    Type of Publication: Journal article published
    PubMed ID: 20046231
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  • 9
    Keywords: CANCER ; COMBINATION ; PHASE-I ; leukemia ; INHIBITORS ; CHROMOSOMES ; DRUG DISCOVERY ; leukemogenesis ; H3K79 METHYLATION ; HISTONE METHYLTRANSFERASE DOT1L
    Abstract: The patent presents 140 purine and 7-azapurine derivatives as potent inhibitors of DOT1L histone methyltransferase that might be useful in the treatment of leukemia with MLL rearrangements. It is becoming more and more evident that the deregulation of chromatin modifiers such as DOT1L plays a critical role in tumorigenesis. As yet, the number of pharmaceutical agents targeting chromatin modifiers is still limited. The market for such compounds has been estimated to be potentially as large as one third of all cancer patients. Overall, the prospective of a targeted product (i.e., a drug targeting a commonly affected chromatin modifier) is very promising, and exponentially growing investments into this market are anticipated.
    Type of Publication: Journal article published
    PubMed ID: 23448241
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