- Synthesis and antitumour evaluation of indole-2-carboxamides against paediatric brain cancer cells
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Paediatric glioblastomas are rapidly growing, devastating brain neoplasms with an invasive phenotype. Radiotherapy and chemotherapy, which are the current therapeutic adjuvant to surgical resection, are still associated with various toxicity profiles and only marginally improve the course of the disease and life expectancy. A considerable body of evidence supports the antitumour and apoptotic effects of certain cannabinoids, such as WIN55,212-2, against a wide spectrum of cancer cells, including gliomas. In fact, we previously highlighted the potent cytotoxic activity of the cannabinoid ligand 5 against glioblastoma KNS42 cells. Taken together, in this study, we designed, synthesised, and evaluated several indoles and indole bioisosteres for their antitumour activities. Compounds 8a, 8c, 8f, 12c, and 24d demonstrated significant inhibitory activities against the viability (IC50 = 2.34-9.06 μM) and proliferation (IC50 = 2.88-9.85 μM) of paediatric glioblastoma KNS42 cells. All five compounds further retained their antitumour activities against two atypical teratoid/rhabdoid tumour (AT/RT) cell lines. When tested against a medulloblastoma DAOY cell line, only 8c, 8f, 12c, and 24d maintained their viability inhibitory activities. The viability assay against non-neoplastic human fibroblast HFF1 cells suggested that compounds 8a, 8c, 8f, and 12c act selectively towards the panel of paediatric brain tumour cells. In contrast, compound 24d and WIN55,212-2 were highly toxic toward HFF1 cells. Due to their structural resemblance to known cannabimimetics, the most potent compounds were tested in cannabinoid 1 and 2 receptor (CB1R and CB2R) functional assays. Compounds 8a, 8c, and 12c failed to activate or antagonise both CB1R and CB2R, whereas compounds 8f and 24d antagonised CB1R and CB2R, respectively. We also performed a transcriptional analysis on KNS42 cells treated with our prototype compound 8a and highlighted a set of seven genes that were significantly downregulated. The expression levels of these genes were previously shown to be positively correlated with tumour growth and progression, indicating their implication in the antitumour activity of 8a. Overall, the drug-like and selective antitumour profiles of indole-2-carboxamides 8a, 8c, 8f, and 12c substantiate the versatility of the indole scaffold in cancer drug discovery. This journal is
- Alsayed, Shahinda S. R.,Bailey, Anders W.,Gunosewoyo, Hendra,Huang, Chiang-Ching,Kassiou, Michael,Lane, Samuel,Sredni, Simone Treiger,Suri, Amreena,Werry, Eryn L.,Yu, Li-Fang
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p. 1910 - 1925
(2022/01/04)
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- Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite Plasmodium falciparum and Optimization Efforts
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A novel diazaspiro[3.4]octane series was identified from a Plasmodium falciparum whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp3-rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure-activity-relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by whole-genome sequencing implicated the P. falciparum cyclic amine resistance locus in the mode of resistance.
- Le Manach, Claire,Dam, Jean,Woodland, John G.,Kaur, Gurminder,Khonde, Lutete P.,Brunschwig, Christel,Njoroge, Mathew,Wicht, Kathryn J.,Horatscheck, André,Paquet, Tanya,Boyle, Grant A.,Gibhard, Liezl,Taylor, Dale,Lawrence, Nina,Yeo, Tomas,Mok, Sachel,Eastman, Richard T.,Dorjsuren, Dorjbal,Talley, Daniel C.,Guo, Hui,Simeonov, Anton,Reader, Janette,Van Der Watt, Mari?tte,Erlank, Erica,Venter, Nelius,Zawada, Jacek W.,Aswat, Ayesha,Nardini, Luisa,Coetzer, Theresa L.,Lauterbach, Sonja B.,Bezuidenhout, Belinda C.,Theron, Anjo,Mancama, Dalu,Koekemoer, Lizette L.,Birkholtz, Lyn-Marie,Wittlin, Sergio,Delves, Michael,Ottilie, Sabine,Winzeler, Elizabeth A.,Smith, Dennis,Fidock, David A.,Street, Leslie J.,Basarab, Gregory S.,Duffy, James,Chibale, Kelly
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supporting information
p. 2291 - 2309
(2021/03/01)
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- 1H-pyrrole[2,3-b]pyridine derivative as well as synthesis method and application thereof
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The invention relates to the technical field of organic synthesis, in particular to a 1H-pyrrole[2,3-b]pyridine derivative as well as a synthesis method and application thereof. The synthesis method comprises the following steps: with p-aminophenylacetic
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Paragraph 0048; 0052-0055
(2020/11/26)
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- Hypoxia-Activated Prodrugs of PERK Inhibitors
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Tumour hypoxia plays an important role in tumour progression and resistance to therapy. Under hypoxia unfolded proteins accumulate in the endoplasmic reticulum (ER) and this stress is relieved through the protein kinase R-like ER kinase (PERK) signalling
- Liew, Lydia P.,Singleton, Dean C.,Wong, Way W.,Cheng, Gary J.,Jamieson, Stephen M. F.,Hay, Michael P.
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p. 1238 - 1248
(2019/02/05)
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- Design and synthesis of (aza)indolyl maleimide-based covalent inhibitors of glycogen synthase kinase 3β
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As an important kinase in multiple signal transduction pathways, GSK-3β has been an attractive target for chemical probe discovery and drug development. Compared to numerous reversible inhibitors that have been developed, covalent inhibitors of GSK-3β are
- Yang, Zhimin,Liu, Hui,Pan, Botao,He, Fengli,Pan, Zhengying
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supporting information
p. 4127 - 4140
(2018/06/12)
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- Pharmacomodulation of the antimalarial plasmodione: Synthesis of biaryl-and N-arylalkylamine analogues, antimalarial activities and physicochemical properties
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With the aim of increasing the structural diversity on the early antimalarial drug plasmodione, an efficient and versatile procedure to prepare a series of biaryl- and N-arylalkylamines as plasmodione analogues is described. Using the naturally occurring and commercially available menadione as starting material, a 2-step sequence using a Kochi-Anderson reaction and subsequent Pd-catalyzed Suzuki-Miyaura coupling was developed to prepare three representative biphenyl derivatives in good yields for antimalarial evaluation. In addition, synthetic methodologies to afford 3-benzylmenadione derivatives bearing a terminal -N(Me)2 or -N(Et)2 in different positions (ortho, meta and para) on the aryl ring of the benzylic chain of plasmodione were investigated through reductive amination was used as the optimal route to prepare these protonable N-arylalkylamine privileged scaffolds. The antimalarial activities were evaluated and discussed in light of their physicochemical properties. Among the newly synthesized compounds, the para-position of the substituent remains the most favourable position on the benzyl chain and the carbamate -NHBoc was found active both in vitro (42 nM versus 29 nM for plasmodione) and in vivo in Plasmodium berghei-infected mice. The measured acido-basic features of these new molecules support the cytosol-food vacuole shuttling properties of non-protonable plasmodione derivatives essential for redox-cycling. These findings may be useful in antimalarial drug optimization.
- Urgin, Karène,Jida, Mouhamad,Ehrhardt, Katharina,Müller, Tobias,Lanzer, Michael,Maes, Louis,Elhabiri, Mourad,Davioud-Charvet, Elisabeth
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- METHODS AND COMPOSITIONS INVOLVING RAD51 INHIBITORS
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The present invention concerns methods and compositions involving inhibitors and of RAD51, a protein involved in homologous recombination. In some embodiments, there are methods for sensitizing cells to the effects of DNA damaging agents, which can have p
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Page/Page column 52; 53
(2014/06/23)
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- An optimized RAD51 inhibitor that disrupts homologous recombination without requiring michael acceptor reactivity
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Homologous recombination (HR) is an essential process in cells that provides repair of DNA double-strand breaks and lesions that block DNA replication. RAD51 is an evolutionarily conserved protein that is central to HR. Overexpression of RAD51 protein is
- Budke, Brian,Kalin, Jay H.,Pawlowski, Michal,Zelivianskaia, Anna S.,Wu, Megan,Kozikowski, Alan P.,Connell, Philip P.
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supporting information
p. 254 - 263
(2013/02/23)
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- INHIBITORS OF P38 MAP KINASE
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Compounds of formula (I) are p38 MAP kinase inhibitors useful for the treatment of autoimmune and inflammatory diseases: wherein: G is -N= or -CH=; D is an optionally substituted divalent mono- or bi-cyclic aryl or heteroaryl radical having 5 - 13 ring members; R6 is hydrogen or optionally substituted CrC3 alkyl; P represents hydrogen and U represents a radical of formula (IA); or U represents hydrogen and P represents a radical of formula (IA); wherein A represents an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members; z is O or 1; -X1-L1-Y- is a linker radical or bond; R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular esterase enzymes to a carboxylic acid group; and R2 and R3 are as defined in the claims.
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Page/Page column 31; 32
(2009/10/21)
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- 2-ARYLCARBOXAMIDE-NITROGENEOUS HETEROCYCLE COMPOUND
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A compound represented bv the formula [I]: [wherein R1 and R2 are the same or different and each represents C1-6 alkyl, C3-8 cycloalkyl, et al; R3a, R3b, and R4 are the same or different and each represents hydrogen, C1-6 alkyl, et al; X represents -N-, -CH-, et al; Y1 represents a single bond, C1-3 alkylene, et al; Y2 represents C1-4 alkylene, oxy(C1-4 alkylene), et al; Ar1 represents a monocyclic aromatic carbocyclic group, monocyclic aromatic heterocyclic group, et al; and Ar2 represents a 5- or 6-membered aromatic carbocyclic group, aromatic heterocyclic group, et al]. This compound functions as a melanin-concentrating hormone receptor antagonist and is useful as, e.g., a therapeutic agent for obesity, et al.
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Page/Page column 27-28
(2008/06/13)
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- COMPOSITIONS AND METHODS COMPRISING PROTEINASE ACTIVATED RECEPTOR ANTAGONISTS
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Compositions and methods comprising proteinase activated receptor antagonists are provided. More particularly, the present invention relates to the use of proteins, peptides and molecules that bind to proteinase activated receptor 2, and inhibit the processes associated with the activation of that receptor. More specifically, the present invention provides novel compositions and methods for the treatment of disorders and diseases such as those associated with abnormal cellular proliferation, angiogenesis, inflammation and cancer.
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Page/Page column 48
(2010/10/20)
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- Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them
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The invention relates to new derivatives of 2-(iminomethyl)amino-phenyl which are NO synthase inhibitors and can trap reactive oxygen species. These compounds can notably be used for the treatment of stroke, of neurodegenerative diseases and of ischemic or hemorragic cardiac or cerebral infarctions. These compounds include: N-{4-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide; N-{3-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide; N-(4-{[{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}(methyl)amino]methyl}phenyl)thiophene-2-carboximidamide; N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide; N-(3-{[(3,5-di-tert-butyl-4-hydroxybenzyl)amino]methyl}phenyl)thiophene-2-carboximidamide; N-[3-({[2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide; N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide; N-(3-{[(4-hydroxy-3,5-diisopropylbenzyl)amino]methyl}phenyl) thiophene-2-carboximidamide; N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide; N-2-(3,5-di-tert-butyl-4-hydroxybenzoyl)-N-1-(4-{[imino(thien-2-yl)methyl]amino}phenyl)-L-leucinamide; and pharmaceutically acceptable salts thereof.
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- Phenylacetamido-thiazole derivatives, process for the preparation and their use as antitumor agents
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Compounds represented by formula (I), as defined in the description, wherein R is a hydrogen atom or a methyl group and R1 is a group as defined in the specification, or a pharmaceutically acceptable salt thereof, are disclosed; the said compounds are use
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- New derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them
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The invention relates to new derivatives of 2-(iminomethyl)amino-phenyl which are NO synthase inhibitors and can trap reactive oxygen species. These compounds can notably be used for the treatment of stroke, of neurodegenerative diseases and of ischemic or hemorragic cardiac or cerebral infarctions. These compounds include: N-{4-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide; N-{3-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide; N-(4-{[{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}(methyl)amino]methyl}phenyl)thiophene-2-carboximidamide; N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl) phenyl]thiophene-2-carboximidamide; N-(3-{[(3,5-di-tert-butyl-4-hydroxybenzyl)amino]methyl}phenyl) thiophene-2-carboximidamide; N-[3-({[2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl]amino}methyl) phenyl]thiophene-2-carboximidamide; N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl) phenyl]thiophene-2-carboximidamide; N-(3-{[(4-hydroxy-3,5-diisopropylbenzyl)amino]methyl}phenyl) thiophene-2-carboximidamide; N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl) phenyl]thiophene-2-carboximidamide; N-2-(3,5-di-tert-butyl-4-hydroxybenzoyl)-N-1-(4-{[imino(thien-2-yl)methyl]amino}phenyl)-L-leucinamide; and pharmaceutically acceptable salts thereof.
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- Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them
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A compound selected from the group consisting of a compound of the formula wherein A is selected from the group consisting of and the other substituents are defined in the specification having an inhibitory activity of NO-synthase enzymes producing nitrogen mono-oxide and/or an activity which traps the reactive oxygen species.
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Page column 86-87
(2008/06/13)
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- Phenylacetamido-pyrazole derivatives, process for their preparation and their use as antitumor agents
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Compounds represented by formula (I) wherein R is a C3-C5cycloalkyl group, R1is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof; are useful in the treatment of cell proliferative disorders, e.g. cancer, associated with an altered cell cycle dependent kinase activity.
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- Synthesis and study of peptides with semirigid i and i+7 side-chain bridges designed for α-helix stabilization
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A search for conformational constraints on the peptide α-helical conformation indicated that para-substituted amino acid derivatives of a benzene ring might be suitable for linking pairs of side chains that are separated by two turns of the helix. A 14-residue synthetic, amphiphilic α-helical peptide model system has been used to study the helix stabilizing effects of a series of four such bridges having constitutionally isomeric structures. These bridges were used to link positions 3 and 10 of the model peptides. The peptides were synthesized in good yield by standard solid-phase methods, including cyclization on the solid support. They were then studied for their solution conformations and melting behavior by circular dichroism (CD) spectropolarimetry, and for their elution behavior on reversed-phase HPLC columns. In aqueous solution and in 50% (v/v) trifluoroethanol, the most effective bridge for helix stabilization consisted of a 4-(aminomethyl)phenylacetic acid residue (AMPA) linked by amide bonds to the side chain functional groups of a (S)-2,3-diaminopropionic acid residue (Dap) in position 3 of the model peptide and an aspartic acid residue in position 10. This Dap3(AMPA), Asp10 bridge was about as effective as two Lys(i), Asp(i+4) lactam bridges incorporated linking residues 3 and 7, and 10 and 14, in the same model peptide sequence. This suggests that it is worth about 1kcal/mol of helix stabilization energy. Copyright (C) 1999 Elsevier Science Ltd.
- Yu, Chongxi,Taylor, John W.
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p. 161 - 175
(2007/10/03)
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- Synthesis and quantitative structure-activity relationships of N-(1- benzylpiperidin-4-yl)phenylacetamides and related analogues as potent and selective σ1 receptor ligands
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A series of N-(1-benzylpiperidin-4-yl)phenylacetamide derivatives was synthesized and evaluated for affinity at σ1 and σ2 receptors. Most of these compounds showed a high affinity for σ1 receptors and a low to moderate aff
- Huang, Yunsheng,Hammond, Philip S.,Whirrett, Brian R.,Kuhner, Ross J.,Wu, Li,Childers, Steven R.,Mach, Robert H.
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p. 2361 - 2370
(2007/10/03)
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- Guanidinophenyl-Substituted Enol Lactones as Selective, Mechanism-Based Inhibitors of Trypsin-like Serine Proteases
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We have synthesized four guanidinophenyl-substituted protio enol and iodo enol lactones (3-(4-guanidinophenyl)-6-methylidenetetrahydro-2-pyranone (1), 3-(4-guanidinophenyl)-6-(E)-(iodomethylidene)tetrahydro-2-pyranone (2), 4-(4-guanidinophenyl)-6-methylidenetetrahydro-2-pyranone (3), and 4-(4-guanidinophenyl)-6-(E)-(iodomethylidene)tetrahydro-2-pyranone (4)) and tested them for inhibitory activity against some trypsin-like enzymes, namely trypsin, urokinase, tissue plasminogen activator (t-PA), plasmin, and thrombin, as well as α-chymotrypsin and human neutrophil elastase (HNE).The β-aryl-substituted protio lactone 3 was a potent alternate substrate inhibitor of trypsin and urokinase.The α-aryl-substituted iodo lactone 2 was a permanent inactivator of urokinase, plasmin, t-PA, thrombin, and α-chymotrypsin, exhibiting a relatively high specificity for the former two enzymes.In general, these compounds showed a preference for inactivating trypsin-like enzymes over α-chymotrypsin and HNE.Also, within the class of trypsin-like enzymes, there was generally good selectivity of inhibition.
- Rai, Roopa,Katzenellenbogen, John A.
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p. 4150 - 4159
(2007/10/02)
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- Substituent effects on an antibody-catalyzed hydrolysis of phenyl esters: Further evidence for an acyl-antibody intermediate
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The hydrolysis of a series of para-substituted phenyl esters (2 and 6a-d) by the monoclonal catalytic antibody NPN43C9 has been investigated. The apparent pKa observed in the kcat/Km-pH profiles shifts from 8.9 (p-nitrophe
- Gibbs, Richard A.,Benkovic, Patricia A.,Janda, Kim D.,Lerner, Richard A.,Benkovic, Stephen J.
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p. 3528 - 3534
(2007/10/02)
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- Anti-thrombotic peptide and pseudopeptide derivatives
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Disclosed are novel peptide and pseudopeptide derivatives and pharmaceutical compositions thereof that inhibit platelet aggregation and thrombus formation in mammalian blood.
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- Electrophilic derivatives of purines as irreversible inhibitors of A1 adenosine receptors
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Functionalized congeners derived from 1,3-dipropyl-8-phenylxanthine and from N6-phenyladenosine were derivatized to contain electrophilic groups (isothiocyanate, N-hydroxysuccinimide ester, maleimide, sulfonyl chloride, or α-haloacyl group) capable of reaction with nucleophiles on biopolymers. The goal was to inhibit chemically the A1 adenosine receptor by using reactive agonist and antagonist ligands. Some of the electrophilic derivatives were synthesized through acylation of amine-functionalized congeners using hetero- or homobifunctional reagents available for protein cross-linking. The affinity for A1 adenosine receptors was evaluated in competitive binding assays by using rat and bovine brain membranes. Several xanthine and adenosine thiourea derivatives prepared from 1,3- and 1,4-phenylene diisothiocyanate (DITC) were potent irreversible inhibitors of adenosine receptors. Derivatives of m-DITC, at concentrations between 10 and 500 nM, irreversibly eliminated binding at 90% of the A1-receptor sites. Receptor affinity of both xanthine and adenosine derivatives containing distal phenylthiourea substituents was diminished by electron-donating groups on the ring.
- Jacobson,Barone,Kammula,Stiles
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p. 1043 - 1051
(2007/10/02)
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