- The preparation of fluorescence-quenched probes for use in the characterization of human factor Xa substrate binding domains
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The preparation and characterization by LCMS of a library of 55 fluorescence-quenched peptides is described. The peptides bear a terminal anthranilamide fluorophore and a penultimate 2,4-dinitrophenyl-L-lysine quencher, and will be used to probe the subst
- Bromfield, Karen M.,Cianci, Julia,Duggan, Peter J.
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Read Online
- TELOMERASE REVERSE TRANSCRIPTASE DEGRADERS AND METHODS OF USE THEREOF
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The present disclosure provides TERT inhibitor compounds, a TERT inhibitor linked to a ubiquitin ligase ligand, as well as pharmaceutical compositions thereof. The present disclosure also provides methods of inhibiting telomerase reverse transcriptase (TERT) and methods of treating or preventing a disease or disorder using said compounds and/or compositions.
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- Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B/NS3 Proteases
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The NS2B/NS3 serine proteases of the Zika and Dengue flaviviruses are attractive targets for the development of antiviral drugs. We report the synthesis and evaluation of a new, proline-based compound class that displays allosteric inhibition of both proteases. The structural features relevant for protease binding and inhibition were determined to establish them as new lead compounds for flaviviral inhibitors. Based on our structure-activity relationship studies, the molecules were further optimized, leading to inhibitors with submicromolar IC50 values and improved lipophilic ligand efficiency. The allosteric binding site in the proteases was probed using mutagenesis and covalent modification of the obtained cysteine mutants with maleimides, followed by computational elucidation of the possible binding modes. In infected cells, antiviral activity against Dengue virus serotype 2 using prodrugs of the inhibitors was observed. In summary, a novel inhibitor scaffold targeting an allosteric site shared between flaviviral NS2B/NS3 proteases is presented whose efficacy is demonstrated in vitro and in cellulo.
- Millies, Benedikt,Von Hammerstein, Franziska,Gellert, Andrea,Hammerschmidt, Stefan,Barthels, Fabian,G?ppel, Ulrike,Immerheiser, Melissa,Elgner, Fabian,Jung, Nathalie,Basic, Michael,Kersten, Christian,Kiefer, Werner,Bodem, Jochen,Hildt, Eberhard,Windbergs, Maike,Hellmich, Ute A.,Schirmeister, Tanja
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p. 11359 - 11382
(2019/12/24)
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- COMPOUND HAVING ZNF143 INHIBITORY ACTIVITY AND USE THEREOF
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PROBLEM TO BE SOLVED: To provide a compound having a ZNF143 inhibitory activity as well as to provide a ZNF143 inhibitory agent and pharmaceutical composition containing the same. SOLUTION: Provided is a compound represented by formula (I) or a salt thereof as well as a ZNF143 inhibitory agent containing the same and a pharmaceutical composition having the same as an active ingredient. A-B-C-D (I)[A is H, a methyl group, a naphthyl group, a phenyl group or a nitrogen-containing heterocyclic ring; B is as shown below, and C is an amide bond or a heteroaromatic ring containing N and O; D is a substituted/unsubstituted phenyl group or a monocyclic heteroaromatic ring containing N or S; and C and D are both fused heterocyclic ring or the like optionally having a substituent group.]. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0354
(2016/10/27)
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- Of the skeleton with dithiazo Pleuromutilin derivatives and the preparation method, application
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The invention discloses a pleuromutilin derivative with a thiadiazole skeleton and a preparation method thereof. The preparation method comprises the following steps: 1, synthesizing 22-O-(4-tosyl)acetoxyl mutilin; 2, synthesizing 14-O-( iodoacetyl)mutili
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Paragraph 0092; 0093; 0095
(2016/12/01)
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- Novel derivatives of 5-amino-1-cyclopropyl-7-[(3R,5S)3,5- dimethylpiperazine-1-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylic acid: Their synthesis, antimicrobial, antifungal, and urease inhibitory studies
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Sparfloxacin (SPFX) or 5-amino-1-cyclopropyl-7-[(3R,5S)3,5- dimethylpiperazine-1-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylic acid is an orally active synthetic, broad spectrum third generation quinolone, with excellent activity against Gram-positive bacteria with selectivity against anaerobes and atypical pathogens. Three derivatives of SPFX (2, 3, and 4) were synthesized by reacting different aromatic carboxylic acids with SPFX (1). Chemistry involved the formation of amide between reacting species through nucleophilic substitution reactions. The synthesized derivatives were then structurally characterized by IR, NMR, and mass spectroscopic techniques. The antimicrobial activities of these derivatives were evaluated against four Gram-positive, seven Gram-negative bacteria, and six fungi, using SPFX as a reference. Statistical analysis revealed these derivatives as active antimicrobial agents, and 2 was more potent antimicrobial agents than the parent drug as well other fluoroquinolones. Compounds 3 and 4 showed a significant activity against Fusarium solani. Moreover, these three derivatives were evaluated for inhibitory activities against enzyme urease, carbonic anhydrase II, and α-chymotrypsin. Results showed their selectivity against urease enzyme. Based on their nontoxic behavior, these derivatives may be potential agents for further studies.
- Arayne, M. Saeed,Sultana, Najma,Gul, Somia,Khan, Ajmal
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p. 1248 - 1256
(2014/03/21)
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- DIHYDROQUINAZOLINONE ANALOGUES AS BRD4 INHIBITORS
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The present invention encompasses compounds of general formula (I) wherein the groups R1 to R4 and A1 to A5 have the meanings given in the claims and in the specification. The compounds of the invention are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation pharmaceutical preparations containing such compounds and their uses as a medicament.
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Page/Page column 46-47
(2014/10/15)
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- DIHYDROQUINAZOLINONE ANALOGUES
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The present invention encompasses compounds of general formula (I) wherein the groups R1 to R4 and A1 to A5 have the meanings given in the claims and in the specification. The compounds of the invention are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation pharmaceutical preparations containing such compounds and their uses as a medicament.
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Paragraph 0211; 0212
(2014/10/16)
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- Synthesis and biological activities of novel pleuromutilin derivatives with a substituted thiadiazole moiety as potent drug-resistant bacteria inhibitors
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A series of novel pleuromutilin derivatives possessing thiadiazole moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by the agar dilution method and Oxford cup assay. The majority of the tested compounds displayed moderate antibacterial activities. Importantly, the three compounds with amino or tertiary amine groups in their side chains, 11, 13b, and 15c, were the most active antibacterial agents. Docking experiments carried out on the peptidyl transferase center (PTC) of 23S rRNA proved that there is a reasonable direct correlation between the binding free energy (ΔGb, kcal/mol) and the antibacterial activity. Moreover, the pharmacokinetic profiles of 11 and 15c in rat were characterized by moderate clearance and oral bioavailability.
- Shang, Ruofeng,Pu, Xiuying,Xu, Ximing,Xin, Zhijun,Zhang, Chao,Guo, Wenzhu,Liu, Yu,Liang, Jianping
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p. 5664 - 5678
(2014/08/05)
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- Ester vs. amide on folding: A case study with a 2-residue synthetic peptide
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Although known for their inferiority as hydrogen-bonding acceptors when compared to amides, esters are often found at the C-terminus of peptides and synthetic oligomers (foldamers), presumably due to the synthetic readiness with which they are obtained using protected peptide coupling, deploying amino acid esters at the C-terminus. When the H-bonding interactions deviate from regularity at the termini, peptide chains tend to "fray apart". However, the individual contributions of C-terminal esters in causing peptide chain end-fraying goes often unnoticed, particularly due to diverse competing effects emanating from large peptide chains. Herein, we describe a striking case of a comparison of the individual contributions of C-terminal ester vs. amide carbonyl as a H-bonding acceptor in the folding of a peptide. A simple two-residue peptide fold has been used as a testing case to demonstrate that amide carbonyl is far superior to ester carbonyl in promoting peptide folding, alienating end-fraying. This finding would have a bearing on the fundamental understanding of the individual contributions of stabilizing/destabilizing non-covalent interactions in peptide folding.
- Vijayadas, Kuruppanthara N.,Nair, Roshna V.,Gawade, Rupesh L.,Kotmale, Amol S.,Prabhakaran, Panchami,Gonnade, Rajesh G.,Puranik, Vedavadi G.,Rajamohanan, Pattuparambil R.,Sanjayan, Gangadhar J.
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supporting information
p. 8348 - 8356
(2013/12/04)
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- A phosgene and peroxide-free one-pot tandem synthesis of isatoic anhydrides involving anthranilic acid, boc anhydride and 2-chloro-N-methyl pyridinium iodide
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A phosgene and peroxide-free approach for the synthesis of isatoic anhydrides has been described. The synthesis involves the carbamate formation with boc anhydride followed by in situ cyclization to afford the isatoic anhydride. The importance of this synthetic strategy is in the ease of operation, scalability and preparation from readily available raw materials.
- Verma, Chhaya,Sharma, Somesh,Pathak, Arunendra
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supporting information
p. 6897 - 6899
(2019/04/10)
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- Synthesis and antibacterial evaluation of novel pleuromutilin derivatives
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A series of novel pleuromutilin derivatives possessing thioether moiety has been synthesized via acylation reaction under mild conditions. Their in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by agar dilution method and Oxford cup assay. Among the 17 compounds screened, 14-O-[(4-methoxybenzamide-2- methylpropane-2-yl) thioacetate] mutilin 4i, 14-O-[(2-aminobenzamide-2- methylpropane-2-yl) thioacetate] mutilin 5a and 14-O-[(4-aminobenzamide-2- methylpropane-2-yl) thioacetate] mutilin 5c were resulted as most active antibacterial agents.
- Shang, Ruofeng,Liu, Yu,Xin, Zhijun,Guo, Wenzhu,Guo, Zhiting,Hao, Baocheng,Jianping, Liang
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p. 231 - 238
(2013/07/27)
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- Intramolecular N-aza-amidoalkylation in association with Witkop-Winterfeldt oxidation as the key step to synthesize Luotonin-A analogues
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An expedient four-step approach for the synthesis of a short library of original analogues of the Topo-I Luotonin-A inhibitor, substituted at their C8- and N15-positions, was investigated. This consists of Rutaecarpines formation, their Witkop-Winterfeldt oxidation followed ultimately with functional adjustment of the pyrroloquinolone intermediates. In the first step of these investigations, Rutaecarpines including the Topo-I poison Evodiamine were obtained via the new tandem N-acylation/aza-amidoalkylation using a nitrogen atom as an internal nucleophile with or without association with a decarboxylation.
- Pin, Frédéric,Comesse, Sébastien,Da?ch, Adam
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scheme or table
p. 5564 - 5571
(2011/08/09)
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- PEG-mediated facile protocol for N-Boc protection of amines
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We have reported an efficient and eco-friendly protocol for the protection of various structurally and electronically divergent aryl and aliphatic amines using (Boc)2O in the presence of PEG-400 at room temperature. The reaction gave excellent
- Siddaiah,Basha,Padma Rao,Viplava Prasad,Suryachendra Rao
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experimental part
p. 1127 - 1129
(2011/02/28)
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- An expeditious, efficient green methodology for the Boc protection of amines and silyl protection of alcohols over tungstophosphoric acid-doped mesoporous silica
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An efficient, chemoselective and eco-friendly protocol for the protection of amines as N-tert-butylcarbamate using (Boc)2O and protection of alcohols as silyl ether using HMDS over tungstophosphoric acid/SBA15 has been developed. Solventless condition, easy work-up, short reaction time, excellent yields and reusability of the catalyst are the striking features of this methodology which can be considered to be one of the better methods for the protection of amines and alcohols.
- Karmakar, Bikash,Banerji, Julie
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experimental part
p. 3855 - 3858
(2010/08/20)
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- Synthesis of a quinolone library from ynones
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A library of 72 quinolones was synthesized from substituted anthranilic acids, using ynone intermediates. These masked β-dicarbonyl synthons allowed cyclization under milder conditions than previously reported quinolone syntheses.
- Ward, Timothy R.,Turunen, Brandon J.,Haack, Torsten,Neuenswander, Benjamin,Shadrick, William,Georg, Gunda I.
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experimental part
p. 6494 - 6497
(2011/02/24)
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- 3-Aminocarbazole Compounds, Pharmaceutical Composition Containing the Same and Method for the Preparation Thereof
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A compound of formula (I), in which R1, R2, R3, R4, R5, R6, X and Y have the meanings indicated in the description, and the pharmaceutically acceptable salts thereof. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof. A method for preparing the abovementioned compound of formula (I) and the pharmaceutically acceptable salts thereof.
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Page/Page column 6
(2008/12/08)
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- PYRIMIDINE KINASE INHIBITORS
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The invention provides novel kinase inhibitors that are useful as therapeutic agents for example in the treatment malignancies where the compounds have the general formula (I) wherein ring A, X, Y, Z, R1, R2, R3, R4, m and n are as defined herein.
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Page/Page column 41-42
(2008/06/13)
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- 3-AMINOCARBAZOLE COMPOUNDS, PHARMACEUTICAL COMPOSITION CONTAINING THE SAME AND METHOD FOR THE PREPARATION THEREOF
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A compound of formula (I), in which R1 , R2, R3, R4, R5, R6, X and Y have the meanings indicated in the description, and the pharmaceutically acceptable salts thereof. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof. A method for preparing the abovementioned compound of formula (I) and the pharmaceutically acceptable salts thereof.
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Page/Page column 18-19
(2010/11/25)
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- A rate enhancement of tert-butoxycarbonylation of aromatic amines with Boc2O in alcoholic solvents
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A rate enhancement of tert-butoxycarbonylation of aromatic amines by Boc2O in alcohols compared to aprotic solvents was demonstrated. Kinetic analysis by NMR suggested that the reaction in CD3OD was faster than in CDCl3 by a factor of 70. Reactions between Boc2O and various aliphatic and aromatic amines in ethanol provided the N-Boc derivatives in good to excellent yields in short reaction times.
- Vilaivan, Tirayut
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p. 6739 - 6742
(2007/10/03)
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- Method for preparing substituted [1,4]diazepino[6,7,1-hi]indol-4-ones
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Method for the preparation of enantiomerically pure diazepino-indolone of formula which comprises the intramolecular cyclization of a product of formula where A, B, X1, X2, Z, Z1, Z2and R are as defined in the d
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Page column 10
(2008/06/13)
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- MULTIDENTATE LIGAND, MULTI-NUCLEUS METAL COMPLEX, METAL COMPLEX CHAIN, METAL COMPLEX INTEGRATED STRUCTURE, AND PREPARATION METHOD THEREOF
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An object of the present invention is typically to provide a metal complex assembly that is applicable to the miniaturization and elaboration of devices and apparatus in information and communication fields, such as arithmetic and logic units, displays and memories, and to provide a novel multidentate ligand which can be used as a suitable raw material for the metal complex assembly. The present invention is as follows. A multidentate ligand includes at least two planar tetradentate coordination sites in one plane, each of the planar tetradentate coordination sites containing four nitrogen-containing groups of at least one of imino, amido and amino groups, and has the nitrogen atoms of the four nitrogen-containing groups as coordinating atoms in one plane. A metal complex assembly has one of two-dimensional and three-dimensional structures and contains metal complex chains and electroconductive wires, the metal complex chains each contain assembled metal complexes, the electroconductive wires each contain molecules serving as at least one of an acceptor and a donor, and the metal complex chains intersect with the electroconductive wires at such positions that the metal complexes and the molecules serving as at least one of an acceptor and a donor are capable of interacting with each other.
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- Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching
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The vascular endothelial growth factor (VEGF) tyrosine kinase receptors KDR and Flt-1 are targets of current interest in anticancer drug research. PTK787/ZK222584 is a potent inhibitor of these enzymes in clinical evaluation as an antiangiogenic agent. The development of a hypothesis concerning the bioactive conformation of this compound has led to the discovery of a new class of potent inhibitors of KDR and Flt-1, the anthranilamides. This could be achieved with a limited experimental effort, which only involved the testing of one archive compound and the synthesis and testing of one appropriate analogue.
- Furet, Pascal,Bold, Guido,Hofmann, Francesco,Manley, Paul,Meyer, Thomas,Altmann, Karl-Heinz
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p. 2967 - 2971
(2007/10/03)
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- Unprecedented direct conversion of N-N and N=N bonds to N-(tert-butyloxy)carbamates
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For the first time a one step direct conversion of aromatic hydrazines and azo compounds to N-(tert-butoxycarbonyl) amines is achieved via reductive cleavage of N-N and N=N bonds using the inexpensive and safe hydride source polymethylhydrosiloxane (PMHS) and di-tert-butyl dicarbonate [(Boc)2O] in the presence of a catalytic amount of 10% Pd-C.
- Chandrasekhar,Raji Reddy,Jagadeeshwar Rao
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p. 1561 - 1562
(2007/10/03)
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- Direct conversion of azides to carbamates and sulfonamides using Fe/NH4Cl: Effect of sonication
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A simple, direct and effective conversion of azides to carbamates and sulfonamides is achieved using Fe/NH4Cl in methanol. The influence of sonication and direct application in solution phase combinatorial chemistry are also studied by developing a 6x4 matrix library. (C) 2000 Elsevier Science Ltd.
- Chandrasekhar,Narsihmulu
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p. 7969 - 7972
(2007/10/03)
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- Novel applications of ethyl glyoxalate with the Ugi MCR
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This letter describes novel high-yielding solution phase preparations of 1,4-benzodiazepine-2,5-dione, diketopiperazine, ketopiperazine and dihydroquinoxalinone libraries via a UDC (Ugi/de-Boc/cyclization) strategy in combination with ethylglyoxalate. The
- Hulme, Christopher,Cherrier
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p. 5295 - 5299
(2007/10/03)
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- Pentafluorophenyl ester activation for the preparation of N,N'-diaroylhydrazines
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Procedures are reported for the preparation of N,N'-diaroylhydrazines using pentafluorophenyl (Pfp) ester activation of aryl carboxylic acids. Mild conditions which avoid intermediate protection of ring substituents, allows the synthesis of both symmetrical and unsymmetrical diaroylhydrazines in high yields. The recent discovery of potent HIV-1 integrase inhibition by N,N'-bis-salicylhydrazine (1) highlights the potential importance of this class of compounds. The stability of pre-activated Pfp ester intermediates and the facility with which N,N'-diaroylhydrazines can be synthesized using this procedure (stirring at room temperature in DMF) may make the method particularly attractive for synthesis of hydrazide libraries.
- Zhao, He,Burke Jr., Terrence R.
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p. 4219 - 4230
(2007/10/03)
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- Solid phase synthesis of chiral 3-substituted quinazoline-2,4-diones
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The synthesis of chiral 3-substituted quinazoline-2,4-diones was performed starting from N-urethane anthranilamides. This synthetic pathway was applied in solid phase, from commercially available anthranilic acid that was bound to hydroxymethyl polystyrene resin via a carbamate linker. In both cases, cyclisation occurred under basic conditions to afford non-racemized quinazolinediones in high purity.
- Gouilleux, Laurent,Fehrentz, Jean-Alain,Winternitz,Martinez, Jean
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p. 7031 - 7034
(2007/10/03)
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- Relaxing substrate specificity in antibody-catalyzed reactions: Enantioselective hydrolysis of N-Cbz-amino acid esters
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For a catalytic antibody to be generally useful for organic synthetic chemistry, it must be able to accept a broad range of substrates, yet retain high selectivity. In this work, we propose a hapten design to endow antibody catalysts with two opposing qualities, such as high enantioselectivity and broad substrate specificity. Racemic hapten 2 induced two separate classes of catalytic antibodies to hydrolyze either the L- or D-isomers of N-Cbz-amino acid esters 1. In the kinetic resolution of racemic ester 9, antibodies 7G12 and 3G2 gave 96% ee of L-10 and 94% ee of D-10, respectively. In addition, antibody 7G12 displayed broad substrate specificity, hydrolyzing the L-esters of Ala (1a), Leu (1b), Norleu (1c), Met (1d), Phe (1e), Val (1f), and phenylglycine (1g) with high enantioselectivity. Antibody 3G2 also hydrolyzed the D-isomers of these esters without sacrificing the enantioselectivity. This observation suggests that the use of haptens that fit snugly into the antigen-combining site, and leave the linker moiety outside, is an effective approach for the generation of catalytic antibodies with high selectivity and broad substrate applicability.
- Tanaka, Fujie,Kinoshita, Keiko,Tanimura, Ryuji,Fujii, Ikuo
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p. 2332 - 2339
(2007/10/03)
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- Conformation of Anthranilic Acid Peptides: Crystal Structure of tert-Butyloxycarbonyl-Anthranilic-Acid-Glycin-Methyl-Ester and Semi-Empirical (AM1) Description of the Ramachandran Map
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Two different molecules are observed in the asymmetric unit of the crystal structure of tert-butyloxycarbonyl-anthranilic-acid-glycin-methyl-ester (1).The whole conformational area (φ and ψ) of the amino acid part of 1 was investigated with the semi-empir
- Feigel, Martin,Lugert, Gerhard,Manero, Javier,Bremer, Matthias
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p. 1109 - 1116
(2007/10/02)
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- Gonadoliberin derivatives containing an aromatic aminocarboxylic acid in the 6-position, pharmaceutical and veterinary compositions containing them and process for preparing same
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The invention relates to novel gonadoliberin nonapeptide ethylamide or decapeptide amide derivatives of the general formula (I), wherein X1 stands for a 2-aminobenzoic or 3-aminobenzoic acid group; X2 stands for a leucyl,
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