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1.
Stephen Nesnow Garret Nelson William T. Padgett Michael H. George Tanya Moore Leon C. King Linda D. Adams Jeffrey A. Ross 《Chemico-biological interactions》2010,186(2):157-165
Benzo[a]pyrene (B[a]P) is a potent human and rodent lung carcinogen. This activity has been ascribed in part to the formation of anti-trans-7,8-dihydroxy-7,8-dihydroB[a]P-9,10-epoxide (BPDE)-DNA adducts. Other carcinogenic mechanisms have been proposed: (1) the induction of apurinic sites from radical cation processes, and (2) the metabolic formation of B[a]P-7,8-quinone (BPQ) that can form covalent DNA adducts or reactive oxygen species which can damage DNA. The studies presented here sought to examine the role of stable BPQ-DNA adducts in B[a]P-induced mouse lung tumorigenesis. Male strain A/J mice were injected intraperitoneally once with BPQ or trans-7,8-dihydroxy-7,8-dihydroB[a]P (BP-7,8-diol) at 30, 10, 3, or 0 mg/kg. Lungs and livers were harvested after 24 h, the DNA extracted and subjected to 32P-postlabeling analysis. Additional groups of mice were dosed once with BPQ or BP-7,8-diol each at 30 mg/kg and tissues harvested 48 and 72 h later, or with B[a]P (50 mg/kg, a tumorigenic dose) and tissues harvested 72 h later. No BPQ or any other DNA adducts were observed in lung or liver tissues 24, 48, or 72 h after the treatment with 30 mg/kg BPQ. BP-7,8-diol gave BPDE-DNA adducts at all time points in both tissues and B[a]P treatment gave BPDE-DNA adducts in the lung. In each case, no BPQ-DNA adducts were detected. Mouse body weights significantly decreased over time after BPQ or BP-7,8-diol treatments suggesting that systemic toxicity was induced by both agents. Model studies with BPQ and N-acetylcysteine suggested that BPQ is rapidly inactivated by sulfhydryl-containing compounds and not available for DNA adduction. We conclude that under these treatment conditions BPQ does not form stable covalent DNA adducts in the lungs or livers of strain A/J mice, suggesting that stable BPQ-covalent adducts are not a part of the complex of mechanisms involved in B[a]P-induced mouse lung tumorigenesis. 相似文献
2.
Maqbool A. Siddiqui Harry Ford Jr. Clifford George Victor E. Marquez 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):235-250
Abstract A new chiral synthesis of the pseudosugar synthon (1R,2S,4R,5S)-1-[(benzyloxy)methyl]-2-tert-butyloxy-4-hydroxybicyclo[3.1.0]hexane (12) is reported. This compound was used as a template for the construction of carbocyclic nucleoside 4, a conformationally rigid analogue of 2′-deoxyaristeromycin. The X-ray structure and 1H NMR analysis confirmed the exclusive North [2′-exo (2E)] conformation of 4 which is vastly different from that of other non-rigid carbocyclic nucleosides. Compound 4 showed good in vitro antiviral activity against human cytomegalovirus and EBV with minimal cytotoxicity. 相似文献
3.
Yoshihiko Shinohara Hiroshi Hasegawa Tomoyoshi Kaneko Yuka Tamura Takao Hashimoto Kimiyoshi Ichida 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(3-4):417-422
Homocysteine plays a key role in several pathophysiological conditions. To assess the methionine–homocysteine kinetics by stable isotope methodology, we developed a simultaneous quantification method of [2H7]methionine, [2H4]methionine, methionine, [2H4]homocysteine and homocysteine in rat plasma by gas chromatography–mass spectrometry (GC–MS). [13C]Methionine and [13C]homocysteine were used as analytical internal standards to account for losses associated with the extraction, derivatization and chromatography. For labeled and non-labeled homocysteine measurements, disulfide bonds between homocysteine and other thiols or proteins were reduced by dithiothreitol. The reduced homocysteine and methionine species were purified by cation-exchange chromatography and derivatized with isobutyl chlorocarbonate in water–ethanol–pyridine. Quantification was carried out by selected ion monitoring of the molecular-related ions of N(O,S)-isobutyloxycarbonyl ethyl ester derivatives on the chemical ionization mode. The intra- and inter-day precision of the assay was less than 6% for all labeled and non-labeled methionine and homocysteine species. The method is sensitive enough to determine pharmacokinetics of labeled methionine and homocysteine. 相似文献
4.
The formation of "Russian doll" complexes consisting of [n]cycloparaphenylenes was predicted using quantum chemistry tools. The electronic structures of multiple inclusion complexes containing up to four macrocycles were explored at the M06-2X/6-31G* level of theory. The binding energy between the macrocycles increases from the center to the periphery of the complex and can be >60?kcal?mol(-1) for macrocycles containing 14 and 19 repeating units. It has been demonstrated that additional electrostatic interactions originating from the asymmetric electron density distribution observed when comparing the concave and convex macrocycle sides are responsible for the high binding energies in these Russian doll complexes. Oxidation or reduction of the Russian doll complexes creates polarons that are delocalized across the complexes. In the case of polaron cations, most of the polarons are localized at the macrocycle with the smallest ionization potential; for polaron anions, the negative charge is localized across the outer rings of the complex. Because anion polarons are more delocalized than cation polarons, the relaxation energies of the polaron anions were found to be smaller than those of the polaron cations. 相似文献
5.
When minced polycystic ovarian tissue was incubated with a mixture of [4-14C]-pregnenolone and [17α-3H]pregnenolone2 and added cofactors for 25, 40 and 60 min, the following metabolites were isolated and characterized: progesterone, 17-hydroxyprogesterone, 17-hydroxypregnenolone, dehydroepiandrosterone, 4-androstenedione, and testosterone; unmetabolized substrates were also recovered. There were increased amounts of progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone, and 4-androstenedione formed as the incubation time increased. 相似文献
6.
《Bioscience, biotechnology, and biochemistry》2013,77(7):1156-1157
N-Linked oligosaccharides were elongated by glycosylation with mannose and galactose residues in the secretory pathway of Schizosaccharomyces pombe. The wild-type S. pombe cells were agglutinated by the additions of not only concanavalin A lectin, which is specific for mannose residues, but also PNA (from Arachis hypogaea) and RCA (Ricinus communis) lectins, which are specific for terminal galactose residues. By PNA-binding selection, we isolated an S. pombe mutant defective in protein glycosylation. The mutant cells, named gmsl, were not agglutinated by PNA or RCA. In contrast, agglutination of the gmsl cells by the addition of concanavalin A was markedly increased. Structural studies on N-linked oligosaccharides from gmsl mutant cells showed that the number of x-l,2-linked galactose residues wes markedly reduced, and unsubstituted x-l,6-linked polymannose outer chains were attached to the core oligosaccharides. 相似文献
7.
James Cook F. Christopher Zusi Matthew D. Hill Haiquan Fang Bradley Pearce Hyunsoo Park Lizbeth Gallagher Ivar M. McDonald Linda Bristow John E. Macor Richard E. Olson 《Bioorganic & medicinal chemistry letters》2017,27(22):5002-5005
We describe an efficient and convergent synthesis of a series of (1′S,2R,4′S)-3H-4′-azaspiro[benzo[4,5]imidazo[2,1-b]oxazole-2,2′-bicyclo[2.2.2]octanes] displaying potency for the α7 nicotinic acetylcholine receptor (nAChR) and good selectivity vs. the related 5-HT3A receptor. 相似文献
8.
Patrick Bertrand François Dole Marcel Asso Bruno Guigliarelli 《Journal of biological inorganic chemistry》2000,5(6):682-691
The question of the existence of a rate-limiting step in the catalytic cycle of Ni-Fe hydrogenases was taken up by using the sets of data available in the case of two specific enzymes: the hydrogenase from Thiocapsa roseopercisina, in which isotope effects have been systematically investigated over a wide pH range, and the enzyme from Desulfovibrio fructosovorans, for which the activities and the redox properties have been studied in two different forms, the wild type and the P238C mutant. When these data are analyzed in the light of appropriate kinetic models, it is concluded that electron transfer and proton transfer are rate limiting in the H2 uptake and H2 evolution reactions, respectively. This proposal is consistent with the data available from other Ni-Fe enzymes. 相似文献
9.
Mi-Yeon Jang Steven De Jonghe Kristien Van Belle Thierry Louat Mark Waer Piet Herdewijn 《Bioorganic & medicinal chemistry letters》2010,20(3):844-847
The synthesis of a new series of 4-N-piperazinyl-thieno[2,3-d]pyrimidines is described. The synthetic route allows introducing structural variety at positions 2, 4 and 6 of the scaffold. Evaluation of their immunosuppressive activity in a Mixed Lymphocyte Reaction (MLR) assay revealed that the most potent compound has an IC50-value of 66 nM and therefore deserves attention for further medicinal chemistry optimization. 相似文献
10.
Kazuo Kamaike Mihoko Takahashi Kazuyuki Utsugi Kazue Tomizuka Yasunori Okazaki Yuri Tamada 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):749-769
Abstract Nucleophilic substitution reactions of 4-azolyl-1 β-P-D-ribofuranosylpyrimidin-2(1H)-one and 6-azolyl-9-β-D-ribofuranosyl-9H-purine derivatives, which were converted from uridine and inosine, with [15N]phthalimide in the presence of triethylamine or DBU gave N 4-phthaloyl[4-15N]cytidine and N 6-phthaloyl[6-15N]- adenosine derivatives, respectively, in high yields. Similar reactions of those azolyl derivatives with succinimide afforded N 4-succinylcytidine and N 6-succinyladenosine derivatives in high yields. The corresponding 2′-deoxyribonucleosides were also synthesized efficiently through the same procedure. 相似文献
11.
Thomas Böhme Christian K. Engel Géraldine Farjot Stefan Güssregen Torsten Haack Georg Tschank Kurt Ritter 《Bioorganic & medicinal chemistry letters》2013,23(16):4685-4691
Racemic cis-1,1-dioxo-5,6-dihydro-[4,1,2]oxathiazine derivative 4a was isolated as an impurity in a sample of a hit from a HTS campaign on 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). After separation by chiral chromatography the 4a-S, 8a-R enantiomer of compound 4a was identified as the true, potent enzyme inhibitor. The cocrystal structure of 4a with human and murine 11ß-HSD1 revealed the unique binding mode of the oxathiazine series. SAR elucidation and optimization in regard to metabolic stability led to monocyclic tetramethyloxathiazines as exemplified by compound 21g. 相似文献
12.
Ga Eun Lee Ho-Sung Lee So Deok Lee Jung-Ho Kim Won-Ki Kim Yong-Chul Kim 《Bioorganic & medicinal chemistry letters》2009,19(3):954-958
Iminium quaternary protoberberine alkaloids (QPA) have been found to be novel P2X7 antagonists. To assess their structure–activity relationships, these compounds were modified at their R1 and R2 groups and assayed for their ability to inhibit the 2′(3′)-O-(4-benzoylbenzoyl)-ATP (BzATP)-induced uptake of fluorescent ethidium by HEK-293 cells stably expressing the human P2X7 receptor, and their ability to inhibit BzATP-induced IL-1β release by differentiated THP-1 cells. Compounds 15a and 15d, with alkyl groups at the R1 position, and especially compound 19h, with the 2-NO2-4,5-dimethoxy-benzyl group at the R2 position, had potent inhibitory efficacy as P2X7 antagonists. 相似文献
13.
Xiaocong M. Ye Andrei W. Konradi Minghua Sun Shendong Yuan Danielle L. Aubele Michael Dappen Darren Dressen Albert W. Garofalo Jacek J. Jagodzinski Lee Latimer Gary D. Probst Hing L. Sham David Wone Ying-zi Xu Daniel Ness Elizabeth Brigham Grace T. Kwong Chris Willtis Guriqbal S. Basi 《Bioorganic & medicinal chemistry letters》2013,23(4):996-1000
Structure–activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted. 相似文献
14.
《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1989,16(3):255-259
The biodistribution of [75Se]BISTAES was studied in guinea pigs. A higher concentration of radioactivity was observed in articular cartilage than in other tissues or organs. A minimal amount of radioactivity was found in the blood, muscle and bone. The compound was excreted rapidly in urine. The target to background ratios were encouraging. [75Se]BISTAES has potential as an articular cartilage imaging agent and further studies in osteoarthritic animals are merited. 相似文献
15.
Kevin Cusack Hamish Allen Agnieszka Bischoff Anca Clabbers Richard Dixon Shannon Fix-Stenzel Michael Friedman Yvette Gaumont Dawn George Thomas Gordon Pintipa Grongsaard Bernd Janssen Yong Jia Maria Moskey Christopher Quinn Andres Salmeron Christine Thomas Grier Wallace Neil Wishart Zhengtian Yu 《Bioorganic & medicinal chemistry letters》2009,19(6):1722-1725
COT (Tpl2 in mice) is a serine/threonine MAP3 kinase that regulates production of TNF-α and other pro-inflammatory cytokines such as IL-1β via the ERK/MAP kinase pathway. As TNF-α and IL-1β are clinically validated targets for therapeutic intervention in rheumatoid arthritis (RA), blocking COT provides a potential avenue for amelioration of disease. Herein we describe identification of a cellular active selective small molecule inhibitor of COT kinase. 相似文献
16.
New series of thiazolo[4,5-d]pyridazin and imidazo[2′,1′:2,3]thiazolo[4,5-d]pyridazin analogues were designed, synthesized and evaluated for their in vitro DHFR inhibition and antitumor activity. Compounds 13 and 43 proved to be DHFR inhibitors with IC50 0.05 and 0.06 μM, respectively. 43 proved lethal to OVCAR-3 Ovarian cancer and MDA-MB-435 Melanoma at IC50 0.32 and 0.46 μM, respectively. The active compounds formed hydrogen bond at DHFR binding site between N1-nitrogen of the pyridazine ring with Glu30; the carbonyl group with Trp24, Arg70 or Lys64; π-cation interaction with Arg22 and π-π interaction with Phe31 residues. Ring annexation of the active 1,3-thiazole ring analogue 13 into the bicyclic thiazolo[4,5-d]pyridazine (18,19) or imidazo[2,1-b]thiazoles (23–25) decreased the DHFR inhibition activity; while the formation of the tricyclic imidazo[2′,1′:2,3]-thiazolo[4,5-d]pyridazine (43–54) increased potency. The obtained model could be useful for the development of new class of DHFR inhibitors. 相似文献
17.
Guido Achermann Theresa M. Ballard Francesca Blasco Pierre-Emmanuel Broutin Bernd Büttelmann Holger Fischer Martin Graf Maria-Clemencia Hernandez Peter Hilty Frédéric Knoflach Andreas Koblet Henner Knust Anke Kurt James R. Martin Raffaello Masciadri Richard H.P. Porter Heinz Stadler Andrew W. Thomas Gerhard Trube Jürgen Wichmann 《Bioorganic & medicinal chemistry letters》2009,19(19):5746-5752
Through iterative design cycles we have discovered a number of novel new classes where the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine was deemed the most promising GABAA α5 inverse agonist class with potential for cognitive enhancement. This class combines a modest subtype binding selectivity with inverse agonism and has the most favourable molecular properties for further lead optimisation towards a central nervous system (CNS) acting medicine. 相似文献
18.
Basem Kanawati Alexander Genest Philippe Schmitt-Kopplin Dieter Lenoir 《Journal of molecular modeling》2012,18(12):5089-5095
The geometries, energies, and electronic properties of the two possible configurations of bis-[dibenzo[a.i]fluorenylidene] were investigated theoretically by density functional theory DFT B3LYP at the UB3LYP/6-311?+?G(2d,p) // UB3LYP/6-31?+?G(d,p) level of theory. According to the performed calculations, it was found that the singlet is 3.4?kcal?mol-1 lower in energy compared to triplet state at room temperature. This gap is compared with those of other alkenes like ethylene, (61.9?kcal?mol-1) tetra-tert-butyethylene, (6.4?kcal?mol-1) and bis-fluorenylidene (19.5?kcal?mol-1). These results confirm the experimental findings of the paramagnetic properties determined by Franzen and Joschek. The low singlet-triplet gap in the case of bis-[dibenzo[a.i]fluorenylidene] is the result of a steric destabilization of the singlet due to strain and stabilization of the triplet electronic state by delocalization of each free electron within each aromatic moiety. This correlates with the special electronic structure of the triplet state of this compound, where facial interaction of two hydrogen atoms lying close to the lobes of each p-orbital occupied with a single electron at the distorted double bond in the triplet electronic state. Figure
a) The singlet form of bis-dibenzo[a.i]fluorenylidene. b) The triplet form of bis-dibenzo[a.i]fluorenylidene. The central dihedral angle around the C=C double bond changes from 53.2° in the singlet electronic structure to 90.0° in the triplet electronic structure. Of great interest is the very low singlet-triplet gap of this electronic system which equals to 3.4 kcal/mol according to calculation by DFT UB3LYP/6-311+G(2d,p) // UB3LYP/6-31+G(d,p) level of theory. 相似文献
19.
Mohammed A.E. Sallam 《Carbohydrate research》1978,67(1):79-89
Dehydration of the hydroxyalkyl chain of 1-phenyl-3-(d-arabino-tetritol-1-yl)pyrazolo[3,4-b]quinoxaline gave the C-nucleoside 3-β-d-erythrofuranosyl-1-phenyl-pyrazolo[3,4-b]quinoxaline (2) in 82% yield. The structure, and the configuration at the anomeric carbon atom, of 2 were elucidated by periodate oxidation, c.d. and n.m.r. spectroscopy, and mass spectrometry. N.m.r.-spectral and c.d. studies revealed that, due to the large size of the heterocyclic base, compound 2 is formed by inversion in the configuration or C-1 of the side chain. The mechanism of the dehydrative cyclization with inversion is discussed. 相似文献
20.
Jakub Toczek Alexis Broisat Pascale Perret Marie-Dominique Desruet Daniel Fagret Laurent M. Riou Catherine Ghezzi 《PloS one》2014,9(7)