- Carbonylation as a novel method for the assembly of pyrazine based oligoamide alpha-helix mimetics
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The design and synthesis of oligoamide α-helix peptidomimetics is reported. The oligoamide type systems are prepared in a modular fashion by coupling the monomers using palladium-catalyzed carbonylation chemistry. This enabled us to use substrates with a low nucleophilicity, leading to previously unreported pyrazine based oligoamide α-helix mimetics. The proof of principle is given by synthesizing a small set of compounds. Various end-capping groups were introduced and also a mixed multimer was successfully prepared.
- Van Mileghem, Seger,Egle, Brecht,Gilles, Philippe,Veryser, Cedrick,Van Meervelt, Luc,De Borggraeve, Wim M.
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Read Online
- Geldanamycin derivative inhibition of HGF/SF-mediated Met tyrosine kinase receptor-dependent urokinase-plasminogen activation
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Ansamycins, including geldanamycin and the derivative 17-allylamino-17- demethoxygeldanamycin, and radicicol are known for their ability to tightly bind to the ATP-binding site of the amino-terminal domain region of heat shock protein 90. We have found that geldanamycin and some of its derivatives can inhibit hepatocyte growth factor/scatter factor-mediated Met tyrosine kinase receptor-dependent urokinase-plasminogen activation at femtomolar levels. Assessment is made of structural requirements for such an activity and evidence is given that distinguishes the target of such an activity from that of heat shock protein 90.
- Shen, Yuehai,Xie, Qian,Norberg, Monica,Sausville, Edward,Vande Woude, George,Wenkert, David
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- Preparation and properties of clickable amino analogues of the duocarmycins: Factors that affect the efficiency of their fluorescent labelling of DNA
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Herein we report the synthesis of three DNA-alkylating amino analogues of the duocarmycins that carry an alkyne functional group suitable for copper-catalysed click chemistry. The alkyne-containing substituents are connected via a side chain position whic
- Tercel, Moana,McManaway, Sarah P.,Liyanage, H. D. Sarath,Pruijn, Frederik B.
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Read Online
- A ortho-nitro phenol and its derivative synthesis method (by machine translation)
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The invention relates to a method for the synthesis of organic compounds, in the existing technology of O-nitrophenol strong acid used in the synthesis process of the serious problem of environmental pollution and the synthesis step longer more complicated problem, the invention provides a ortho-nitro phenol and synthetic method of derivative thereof, proceeding by the phenol compound, synthesis of 2 - (phenoxy) pyridine, the obtained product, catalyst, tert-butyl nitrite, organic solvent and adding sealing in the pressure containers, in oil bath heating 50 - 100 °C, reaction 10 - 30 hours, to obtain 2 - (2 - nitrobenzene) ethoxy pyridine; re-processing by the ortho-nitro phenol and its derivatives; the method is simple, high-efficiency. (by machine translation)
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Paragraph 0066-0067
(2017/08/23)
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- An ortho-nitro phenol synthetic method of compound
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The invention relates to a synthesis method of o-nitrophenol compounds, solving the problems that production hazards are easily caused due to the release of a large deal of heat during the synthesis of o-nitrophenol and the severe environment pollution caused due to the generation of a large deal of waste gas and acid in the process in the prior art. The invention provides the synthesis method of the o-nitrophenol compounds, which comprises the steps: synthesizing 2-(phenoxy)pyridine from phenol compounds; and then sequentially adding 2-(phenoxy)pyridine and a catalyst, a nitrating reagent, an oxidant and an organic solvent into a sealed pressure container, heating and reacting for 10-50 hours in an oil bath of which the temperature is 80 DEG C-130 DEG C to obtain 2-(2-nitrophenyl)oxy pyridine; and finally treating to obtain o-nitrophenol. The synthesis method is simple, convenient and efficient.
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Paragraph 0066; 0067; 0068
(2016/10/10)
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- Enhanced treatment regimens using mTor inhibitors
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The present invention provides for methods and pharmaceutical compositions comprising inhibitors of mTorC1 and/or mTorC2. In some aspects, the invention provides for treatment regimens resulting in enhanced treatment efficacy and better tolerability.
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Page/Page column 116
(2015/11/27)
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- Palladium-catalyzed aromatic C-H bond nitration using removable directing groups: Regiospecific synthesis of substituted o -nitrophenols from related phenols
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A general and regiospecific transformation of substituted phenols into the related o-nitrophenols has been achieved via a three-step process involving the palladium-catalyzed chelation-assisted ortho-C-H bond nitration as the key step. In the process, 2-pyridinyloxy groups act as removable directing groups for the palladium-catalyzed ortho-nitration of substituted 2-phenoxypridines, and they can be readily removed in the subsequent conversion of the resulting 2-(2-nitrophenoxy)pyridines into 2-nitrophenols.
- Zhang, Wei,Zhang, Jian,Ren, Shaobo,Liu, Yunkui
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p. 11508 - 11516
(2015/01/09)
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- COMBINATION OF KINASE INHIBITORS AND USES THEREOF
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The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3 -kinase α and/or mTOR in a subject.
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Paragraph 00502
(2014/10/04)
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- COMBINATION PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
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The present invention provides for methods and pharmaceutical compositions for treating proliferative disorders. In one aspect, the method comprises administration of two cell-cycle suppressors having a synergistic effect. In another aspect, two cell-cycle suppressors having a synergistic effect are provided in a pharmaceutical composition.
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Paragraph 0485
(2014/12/09)
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- Synthesis and in vitro antimycobacterial and isocitrate lyase inhibition properties of novel 2-methoxy-2′-hydroxybenzanilides, their thioxo analogues and benzoxazoles
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A new series of 2-methoxy-2′-hydroxybenzanilide derivatives and their thioxo analogues have been synthesised and characterised by IR, NMR and elemental analysis. These compounds were investigated for their in vitro antimycobacterial activities against Mycobacterium tuberculosis 331/88, Mycobacterium avium 330/88, Mycobacterium kansasii 235/80, clinically isolated M. kansasii 6509/96 and the ability to act as in vitro isocitrate lyase inhibitors. The best ICL inhibitors were two compounds from the thiobenzanilide group (8f, 8m), which exhibited an inhibition potential that was equal to the standard compound, 3-nitropropionic acid. In addition, the best antimycobacterial properties were exhibited by benzanilide derivatives 6h, 6k and 6l with 5-Cl and 4′ or 5′ Cl/Br substitution. For all the thiobenzanilide derivatives tested, two conformers were observed in the NMR spectra, which is most likely due to the hindered rotation of the C-N bond.
- Kozic, Ján,Novotná, Eva,Volková, Marie,Stola?íková, Ji?ina,Trejtnar, Franti?ek,Wsól, Vladimír,Vin?ová, Jarmila
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p. 108 - 119
(2013/01/15)
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- DNA-dependent protein kinase (DNA-PK) inhibitors: Structure-activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain
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Introduction of an O-alkoxyphenyl substituent at the 8-position of the 2-morpholino-4H-chromen-4-one pharmacophore enabled regions of the ATP-binding site of DNA-dependent protein kinase (DNA-PK) to be probed further. Structure-activity relationships have been elucidated for inhibition of DNA-PK and PI3K (p110α), with N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H- chromen-8-yl)phenyl)-2-morpholinoacetamide 11a being identified as a potent and selective DNA-PK inhibitor (IC50 = 8 nM).
- Clapham, Kate M.,Bardos, Julia,Finlay, M. Raymond V.,Golding, Bernard T.,Griffen, Edward J.,Griffin, Roger J.,Hardcastle, Ian R.,Menear, Keith A.,Ting, Attilla,Turner, Paul,Young, Gail L.,Cano, Céline
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scheme or table
p. 966 - 970
(2011/03/20)
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- High-efficiency tris(8-hydroxyquinoline)aluminum (Alq3) complexes for organic white-light-emitting diodes and solid-state lighting
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Combinations of electron-withdrawing and -donating substituents on the 8-hydroxyquinoline ligand of the tris(8-hydroxyquinoline)aluminum (Alq 3) complexes allow for control of the HOMO and LUMO energies and the HOMO-LUMO gap responsible for emission from the complexes. Here, we present a systematic study on tuning the emission and electroluminescence (EL) from Alq3 complexes from the green to blue region. In this study, we explored the combination of electron-donating substituents on C4 and C6. Compounds 1-6 displayed the emission tuning between 478 and 526 nm, and fluorescence quantum yield between 0.15 and 0.57. The compounds 2-6 were used as emitters and hosts in organic light-emitting diodes (OLEDs). The highest OLED external quantum efficiency (EQE) observed was 4.6 %, which is among the highest observed for Alq3 complexes. Also, the compounds 3-5 were used as hosts for red phosphorescent dopants to obtain white light-emitting diodes (WOLED). The WOLEDs displayed high efficiency (EQE up to 19 %) and high white color purity (color rendering index (CRI≈85). Whiter than white: Electron-withdrawing and -donating substituents on the tris(8-hydroxyquinoline) AlIII (Alq3) complexes allow for control of the emission and electroluminescence from green (526 nm) to the blue region (487 nm), and of the fluorescence quantum yield (0.15-0.57). The compounds used as emitters in OLEDs show a maximum external quantum efficiency (EQE) of 4.6 %, which is among the highest observed for Alq3 complexes. The complexes were used in white-light emitting OLEDs achieving high efficiency (EQE ≈19 %) and high white color purity (CRI≈85).
- Perez-Bolivar, Cesar,Takizawa, Shin-Ya,Nishimura, Go,Montes, Victor A.,Anzenbacher, Pavel
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supporting information; experimental part
p. 9076 - 9082
(2011/10/01)
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- EPIMINOCYCLOALKYL(B)INDOLE DERIVATIVES AS SEROTONIN SUB-TYPE 6 (5-HT6) MODULATORS AND USES THEREOF
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The present invention relates to epiminocycloalkyl[b]indole derivatives as serotonin sub-type 6 (5-HT6) modulators, pharmaceutical compositions including these compounds, and methods of preparation and use thereof. These compounds are useful in the treatment of central nervous system disorders including obesity, metabolic syndrome, cognition, and schizophrenia. The subject compounds have the structure of formula (I), with the substituents being described herein.
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Page/Page column 107
(2011/04/26)
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- BENZOXAZOLE KINASE INHIBITORS AND METHODS OF USE
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The present invention provides chemical entities or compounds and pharmaceutical compositions thereof that are capable of modulating certain protein kinases such as mTor, tyrosine kinases, and/or lipid kinases such as PI3 kinase. Also provided in the present invention are methods of using these compositions to modulate activities of one or more of these kinases, especially for therapeutic applications.
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Page/Page column 134
(2010/05/14)
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- DIAGNOSTIC AND REMEDY FOR DISEASE CAUSED BY AMYLOID AGGREGATION AND/OR DEPOSITION
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To provide a diagnostic drug which binds specifically to an amyloid aggregate and/or an amyloid deposit, to thereby realize imaging and quantification of a disease caused by amyloid aggregation and/or deposition. The invention provides a compound represented by formula (1) : (wherein X1 represents an optionally substituted bicyclic heterocyclic group; X2 represents a hydrogen atom, a halogen atom, or a chelate-forming group; ring A represents a benzene ring or a pyridine ring; and ring B represents an optionally substituted 5-membered aromatic heterocyclic group which is bonded to the benzene ring or the pyridine ring via a carbon atom of ring B), a salt thereof, a solvate of any of these, or a transition metal coordination compound of any of these, and a diagnostic, preventive, or therapeutic drug containing the same.
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(2008/12/07)
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- PROTEIN KINASE INHIBITORS
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Compounds that inhibit protein kinases, compositions containing the compounds and methods of treating diseases using the compounds are disclosed.
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(2010/11/28)
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- GELDANAMYCIN AND DERIVATIVES INHIBIT CANCER INVASION AND IDENTIFY NOVEL TARGETS
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Geldanamycin derivatives that block the uPA-plasmin network and inhibit growth and invasion by glioblastoma cells and other tumors at femtomolar concentrations are potentially highly active anti-cancer drugs. GA and various 17-amino-17-demethoxygelddanamycin derivatives are disclosed that block HGF/SF-mediated Met tyrosine kinase receptor-dependent uPA activation at fM levels. Other ansamycins (macbecins I and II), GA derivatives, and radicicol required concentrations several logs higher (≥nM) to achieve such inhibition. The inhibitory activity of tested compounds was discordant with the known ability of drugs of this class to bind to hsp90, indicating the existence of a novel target(s) for HGF/SF -mediated events in tumor development. Methods of using such compounds to inhibit cancer cell activities and to treat tumors are disclosed. Such treatment with low doses of these highly active compounds provide an option for treating various Met-expressing tumors, in particular invasive brain cancers, either alone or in combination with conventional surgery, chemotherapy, or radiotherapy.
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Page/Page column 39; 40
(2008/06/13)
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- Thrombopoietin mimetics
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Invented are non-peptide TPO mimetics. Also invented are novel processes and intermediates used in the preparation of the presently invented compounds. Also invented is a method of treating thrombocytopenia, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a selected hydroxy-1-azobenzene derivative.
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- Hydroxylation of Nitroarenes with Alkyl Hydroperoxide Anions via Vicarious Nucleophilic Substitution of Hydrogen
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Rhone-Poulenc Polska Ltd., ul. Grzybowska 80/82, 00-844 Warszawa, Poland Garbo- and heterocyclic nitroarenes react with anions of tert-butyl and cumyl hydroperoxides in the presence of strong bases to form substituted o- and p-nitrophenols. The reaction usually proceeds in high yields and is of practical value as a method of synthesis and manufacturing of nitrophenols. Orientation of the hydroxylation can be controlled to a substantial extent by selection of the proper conditions. Basic mechanistic features of this process were clarified.
- Makosza, Mieczyslaw,Sienkiewicz, Krzysztof
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p. 4199 - 4208
(2007/10/03)
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- Synthesis of Mercapturic Acid Derivatives of Putative Toxic Metabolites of Bromobenzene
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The synthesis and characterization of nine isomerically defined S-arylmercapturic acids of interest in connection with the metabolism of the model hepatotoxin bromobenzene is described.Included are three S-(bromophenyl)-, two S-(bromohydroxyphenyl)-, and three S-(bromodihydroxyphenyl)mercapturic acids of defined substitution pattern.In addition, several related compounds with two or no bromine atoms are described.These syntheses depend on two basic methods, 1,4-addition of various arene thiols to acetamidoacrylic acid or the 1,4-addition of N-acetyl-L-cysteine to various benzoquinone derivatives.In addition, we describe a method for efficient conversion of the mercapturic acids to thioanisole derivatives, regioisomers of which can be separed and detected at low levels by capillary gas-liquid chromatography.
- Hanzlik, Robert P.,Weller, Paul E.,Desai, Jayant,Zheng, Jiang,Hall, Larry R.,Slaughter, Donald E.
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p. 2736 - 2742
(2007/10/02)
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- REACTION OF AROMATIC COMPOUNDS WITH NUCLEOPHILIC REAGENTS IN LIQUID AMMONIA. V. THE MECHANISM AND DIRECTION OF HYDROXYLATION OF p-SUBSTITUTED NITROBENZENES WITH POTASSIUM HYDROXIDE
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In the reaction of p-substituted nitrobenzenes 4-XC6H4NO2 (X = Cl, Br, I) with potassium hydroxide and oxygen in liquid ammonia (-33 deg C) the corresponding 5-substituted 2-nitrophenols are formed with high yields.Under analogous conditions 4-fluoronitrobenzene and 1,4-dinitrobenzene are converted into 4-nitrophenol.When K18OH was used, the hydroxyl group of the reaction products contained the 18O isotope preferentially in both cases.The action of KO2 and K2O2 in the presence of oxygen on 4-chloronitrobenzene or of oxygen on the product from the reduction of 4-chloronitrobenzene with potassium leads to the formation of 4-nitrophenol.This set of experimental data agrees with the scheme for the hydroxylation of p-substituted nitrobenzenes with alkali and oxygen in liquid ammonia involving the formation of anionic ? complexes for both directions of the process and their oxidation by molecular oxygen in the case of substitution of a hydrogen atom.
- Malykhin, E. V.,Kolesnichenko, G. A.,Shteingarts, V. D.
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p. 1048 - 1056
(2007/10/02)
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