- New non-symmetrical choline kinase inhibitors
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Identification of novel and selective anticancer agents remains an important and challenging goal in pharmacological research. Choline kinase (ChoK) is the first enzyme in the CDP-choline pathway that synthesizes phosphatidylcholine (PC), the major phosph
- Schiaffino-Ortega, Santiago,López-Cara, Luisa Carlota,Ríos-Marco, Pablo,Carrasco-Jimenez, Maria Paz,Gallo, Miguel A.,Espinosa, Antonio,Marco, Carmen,Entrena, Antonio
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Read Online
- Design of Trifluoroalkenyl Iodonium Salts for a Hypervalency-Aided Alkenylation–Cyclization Strategy: Metal-Free Construction of Aziridine Rings
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The synthesis of fluorinated compounds and their use as pharmaceutical ingredients or synthetic building blocks have been in the focus of chemical and medicinal research. However, the efficient synthesis of trifluoromethylated nitrogen heterocycles is sometimes challenging. Herein, we disclose a simple aziridination process that relies on the use of amines and novel alkenyl iodonium reagents for the synthesis of strained, trifluoromethylated heterocycles. With the utilization of a newly designed and bench-stable but highly reactive hypervalent alkenyl iodonium species, these three-membered-ring heterocyclic compounds can be efficiently constructed from simple amines under mild conditions in the absence of transition-metal catalysts. The special reactivity of the new trifluoropropenyl synthon towards nucleophilic centers could be exploited in more general cyclization and alkenylation reactions in the future.
- Mészáros, ádám,Székely, Anna,Stirling, András,Novák, Zoltán
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Read Online
- Convenient synthesis of deazaflavin cofactor FO and its activity in F420-dependent NADP reductase
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F420 and FO are phenolic 5-deazaflavin cofactors that complement nicotinamide and flavin redox coenzymes in biochemical oxidoreductases and photocatalytic systems. Specifically, these 5-deazaflavins lack the single electron reactivity with O2 of riboflavin-derived coenzymes (FMN and FAD), and, in general, have a more negative redox potential than NAD(P)+. For example, F420-dependent NADP+ oxidoreductase (Fno) is critical to the conversion of CO2 to CH4 by methanogenic archaea, while FO functions as a light-harvesting agent in DNA repair. The preparation of these cofactors is an obstacle to their use in biochemical studies and biotechnology. Here, a convenient synthesis of FO was achieved by improving the redox stability of synthetic intermediates containing a polar, electron-rich aminophenol fragment. Improved yields and simplified purification techniques for FO are described. Additionally, Fno activity was restored with FO in the absence of F420. Investigating the FO-dependent NADP+/NADPH redox process by stopped-flow spectrophotometry, steady state kinetics were defined as having a Km of 4.00 ± 0.39 μM and a kcat of 5.27 ± 0.14 s-1. The preparation of FO should enable future biochemical studies and novel uses of F420 mimics.
- Hossain, Mohammad S.,Le, Cuong Q.,Joseph, Ebenezer,Nguyen, Toan Q.,Johnson-Winters, Kayunta,Foss, Frank W.
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Read Online
- Phosphorylated 3-heteroarylcoumarins and their use in fluorescence microscopy and nanoscopy
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Photostable and bright fluorescent dyes with large Stokes shifts are widely used as markers in far-field optical microscopy, but the variety of useful dyes is limited. The present study introduces new 3-heteroaryl coumarins decorated with a primary phosph
- Nizamov, Shamil,Willig, Katrin I.,Sednev, Maksim V.,Belov, Vladimir N.,Hell, Stefan W.
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Read Online
- Structure-activity relationships of natural quinone vegfrecine analogs with potent activity against VEGFR-1 and -2 tyrosine kinases
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A series of analogs of vegfrecine, a natural quinone vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, was synthesized via oxidative amination of 2,5-dihydroxybenzamide with functionalized arylamine followed by ammonolysis and
- Adachi, Hayamitsu,Nosaka, Chisato,Atsumi, Sonoko,Nakae, Koichi,Umezawa, Yoji,Sawa, Ryuichi,Kubota, Yumiko,Nakane, Chie,Shibuya, Masabumi,Nishimura, Yoshio
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p. 734 - 742
(2021/07/25)
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- SUBSTITUTED AMIDE COMPOUNDS USEFUL AS FARNESOID X RECEPTOR MODULATORS
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Disclosed are compounds of Formula (I): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is: (i) halo, cyano, hydroxyl, NRxRx, C(O)OH, C(O)NH2, C1-6 alkyl substituted with zero to 6 R1a, or P(O)R1cR1c; or (ii) L R1; and A, X1, X2, X3, X4, Z1, Z2, R1, R1a, R1c, R2, R3a, R3b, Rx, L, a, b, and d are defined herein. Also disclosed are methods of using these compounds to modulate the activity of farnesoid X receptor (FXR); pharmaceutical compositions comprising these compounds; and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.
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Page/Page column 204; 205
(2020/08/28)
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- Compound
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PROBLEM TO BE SOLVED: To provide a compound capable of forming a color filter excellent in heat resistance. SOLUTION: The present invention provides a compound represented by formula (I). [In formula (I), R1-R8 independently represen
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Paragraph 0275-0277
(2020/05/02)
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- COMPOUNDS AND METHODS TO ATTENUATE TUMOR PROGRESSION AND METASTASIS
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This invention relates to certain compounds or pharmaceutically acceptable salts thereof, and for the use of the compounds to treat cancer. In another aspect, the disclosure relates to a pharmaceutical composition comprising a compound of Formula (1), For
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Paragraph 0296-0298
(2020/05/28)
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- Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD?Yap Protein-Protein Interaction
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The Hippo pathway coordinates extracellular signals onto the control of tissue homeostasis and organ size. Hippo signaling primarily regulates the ability of Yap1 to bind and co-activate TEA domain (TEAD) transcription factors. Yap1 tightly binds to TEAD4
- Bum-Erdene, Khuchtumur,Zhou, Donghui,Gonzalez-Gutierrez, Giovanni,Ghozayel, Mona K.,Si, Yubing,Xu, David,Shannon, Harlan E.,Bailey, Barbara J.,Corson, Timothy W.,Pollok, Karen E.,Wells, Clark D.,Meroueh, Samy O.
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p. 378 - 13,389
(2019/03/19)
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- Synthesis and in vitro evaluation of diverse heterocyclic diphenolic compounds as inhibitors of DYRK1A
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Dual-specificity tyrosine phosphorylation-related kinase 1A (DYRK1A) is a dual-specificity protein kinase that catalyses phosphorylation and autophosphorylation. Higher DYRK1A expression correlates with cancer, in particular glioblastoma present within the brain. We report here the synthesis and biological evaluation of new heterocyclic diphenolic derivatives designed as novel DYRK1A inhibitors. The generation of these heterocycles such as benzimidazole, imidazole, naphthyridine, pyrazole-pyridines, bipyridine, and triazolopyrazines was made based on the structural modification of the lead DANDY and tested for their ability to inhibit DYRK1A. None of these derivatives showed significant DYRK1A inhibition but provide valuable knowledge around the importance of the 7-azaindole moiety. These data will be of use for developing further structure-activity relationship studies to improve the selective inhibition of DYRK1A.
- Zhou, Qingqing,Reekie, Tristan A.,Abbassi, Ramzi H.,Indurthi Venkata, Dinesh,Font, Josep S.,Ryan, Renae M.,Munoz, Lenka,Kassiou, Michael
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p. 5852 - 5869
(2018/11/10)
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- Structural Optimization and Pharmacological Evaluation of Inhibitors Targeting Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases (DYRK) and CDC-like kinases (CLK) in Glioblastoma
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The DYRK family contains kinases that are up-regulated in malignancy and control several cancer hallmarks. To assess the anticancer potential of inhibitors targeting DYRK kinases, we developed a series of novel DYRK inhibitors based on the 7-azaindole scaffold. All compounds were tested for their ability to inhibit DYRK1A, DYRK1B, DYRK2, and the structurally related CLK1. The library was screened for anticancer efficacy in established and stem cell-like glioblastoma cell lines. The most potent inhibitors (IC50 ≤ 50 nM) significantly decreased viability, clonogenic survival, migration, and invasion of glioblastoma cells. Target engagement was confirmed with genetic knockdown and the cellular thermal shift assay. We demonstrate that DYRK1A’s thermal stability in cells is increased upon compound treatment, confirming binding in cells. In summary, we present synthesis, structure-activity relationship, and efficacy in glioblastoma-relevant models for a library of novel 7-azaindoles.
- Zhou, Qingqing,Phoa, Athena F.,Abbassi, Ramzi H.,Hoque, Monira,Reekie, Tristan A.,Font, Josep S.,Ryan, Renae M.,Stringer, Brett W.,Day, Bryan W.,Johns, Terrance G.,Munoz, Lenka,Kassiou, Michael
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p. 2052 - 2070
(2017/03/17)
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- BICYCLIC HETEROCYCLE DERIVATIVES AS BROMODOMAIN INHIBITORS
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The invention relates to novel bicyclic heterocycle derivatives of formula (I) wherein Cy1,Cy2, R1,R2 and L have the meaning given in the specification, and pharmaceutically acceptable salts thereof. The compounds of formula (I) are usefulas bromodomain inhibitors in the treatment or prevention of diseases or disorders where bromodomain inhibition is desired.
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Page/Page column 39; 40
(2017/01/23)
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- Palladium-Catalyzed Synthesis of Pyrayaquinones, Murrayaquinones, and Murrayafoline-B
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We describe the total synthesis of murrayafoline-B and seven carbazole-1,4-quinone alkaloids. A palladium(II)-catalyzed oxidative cyclization is used to construct the carbazole skeleton. Pyran annulation and oxidation provide pyrayaquinone-A, -B, and -C. DIBAL-H-promoted reductive ring opening of pyrano[3,2-a]carbazole precursors leads to the prenylated and geranylated carbazole-1,4-quinone alkaloids murrayaquinone-B, -C, -D, and -E and to murrayafoline-B.
- Kutz, Sebastian K.,Schmidt, Arndt W.,Kn?lker, Hans-Joachim
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p. 275 - 292
(2016/12/24)
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- Thermally Induced Denitrogenative Annulation for the Synthesis of Dihydroquinolinimines and Chroman-4-imines
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A rapid growth in synthetic methods for the preparation of diverse organic molecules using N-sulfonyl-1,2,3-triazoles is of great interest in organic synthesis. Transition metals are generally used to activate the α-imino diazo intermediates. Metal-free methods have not been studied in detail, but can be a good complement to transition metal catalysis in the mild reaction conditions. We herein report a novel method for the preparation of 2,3-dihydroquinolin-4-imine and chroman-4-imine analogs from their corresponding N-sulfonyl-1,2,3-triazoles in the absence of metal catalysts. To achieve intramolecular annulation, the introduction of an electron-donating group is required at the meta position of N-sulfonyl-1,2,3-triazole methyl anilines. The inclusion of tailored substituents on the aniline moieties and nitrogen atoms enhances the nucleophilicity of the phenyl π-electrons, thus allowing them to undergo a Friedel-Crafts-type reaction with the highly electrophilic ketenimines. This metal-free method was carefully optimized to generate a variety of dihydroquinolin-4-imines and chroman-4-imines in moderate-to-good yields.
- Chou, Chih-Hung,Chen, Ying-Yu,Rajagopal, Basker,Tu, Hsiu-Chung,Chen, Kuan-Lin,Wang, Sheng-Fu,Liang, Chien-Fu,Tyan, Yu-Chang,Lin, Po-Chiao
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supporting information
p. 757 - 765
(2016/03/09)
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- Fatty Acid Amide Hydrolase (FAAH), Acetylcholinesterase (AChE), and Butyrylcholinesterase (BuChE): Networked Targets for the Development of Carbamates as Potential Anti-Alzheimer's Disease Agents
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The modulation of the endocannabinoid system is emerging as a viable avenue for the treatment of neurodegeneration, being involved in neuroprotective and anti-inflammatory processes. In particular, indirectly enhancing endocannabinoid signaling to therapeutic levels through FAAH inhibition might be beneficial for neurodegenerative disorders such as Alzheimer's disease, effectively preventing or slowing the progression of the disease. Hence, in the search for a more effective treatment for Alzheimer's disease, in this paper, the multitarget-directed ligand paradigm was applied to the design of carbamates able to simultaneously target the recently proposed endocannabinoid system and the classic cholinesterase system, and achieve effective dual FAAH/cholinesterase inhibitors. Among the two series of synthesized compounds, while some derivatives proved to be extremely potent on a single target, compounds 9 and 19 were identified as effective dual FAAH/ChE inhibitors, with well-balanced nanomolar activities. Thus, 9 and 19 might be considered as new promising candidates for Alzheimer's disease treatment.
- Montanari, Serena,Scalvini, Laura,Bartolini, Manuela,Belluti, Federica,Gobbi, Silvia,Andrisano, Vincenza,Ligresti, Alessia,Di Marzo, Vincenzo,Rivara, Silvia,Mor, Marco,Bisi, Alessandra,Rampa, Angela
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supporting information
p. 6387 - 6406
(2016/07/26)
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- ANTI-INFLAMMATORY COMPOUND HAVING INHIBITORY ACTIVITY AGAINST MULTIPLE TYROSINE KINASES AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
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The present invention is for the anti-inflammatory compounds that have an inhibitory activity against protein tyrosine kinases and their pharmaceutical composition(s) containing the compound as the active ingredient. Since the compounds of the present invention can inhibit multiple protein kinases associated with inflammatory diseases and immune disorders, they are useful for their prevention or treatment.
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Paragraph 0208-0210
(2013/03/28)
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- FLUORESCENT DYES WITH PHOSPHORYLATED HYDROXYMETHYL GROUPS AND THEIR USE IN LIGHT MICROSCOPY AND IMAGING TECHNIQUES
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The invention relates to novel fluorescent dyes with phosphorylated hydroxymethyl groups, a method for preparing the same as well as to their use in imaging techniques. Said fluorescent dyes are coumarin, rhodamine or BODIPY dyes having of one of the foll
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Page/Page column 24; 38
(2013/05/09)
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- Total synthesis of (±)-cycloclavine and (±)-5-epi- cycloclavine
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Novel routes to the naturally occurring indole alkaloid cycloclavine and its unnatural C(5)-epimer are described. Key features include the rapid construction of the heterocyclic core segments by two Diels-Alder reactions. An indole annulation was accompli
- Petronijevic, Filip R.,Wipf, Peter
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supporting information; experimental part
p. 7704 - 7707
(2011/07/06)
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- Titanocene(III)-catalyzed conversion of N-(epoxyalkyl)anilines into indolines
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Densely substituted indolines and azaindolines can be obtained by the titanocene(III) chloride catalyzed reductive opening of N-(oxiran-2-ylmethyl) anilines. The reaction optimization, substrate scope, and limitations are discussed, and a mechanistic pathway for the epoxideopening rearrangement is proposed. ARKAT-USA, Inc.
- MacIejewski, John P.,Wipf, Peter
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experimental part
p. 92 - 119
(2011/06/20)
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- THIAZOLIDINONE COMPOUNDS, AND METHODS OF MAKING AND USING SAME
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Provided herein are thiazolidinone compounds, and methods of making and using the same. Such compounds may be used in inflammatory or immune-mediated disorders. The disclosure provides for treating respiratory or ocular disorders, treating arthritis, or may be used to treat cancer, such as prostate or breast cancer, or multiple myeloma.
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Page/Page column 63
(2009/04/25)
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- Design, synthesis, and structure - Activity relationship of indole-3-glyoxylamide libraries possessing highly potent activity in a cell line model of prion disease
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Transmissible spongiform encephalopathies (TSEs) are a family of invariably fatal neurodegenerative disorders for which no effective curative therapy currently exists. We report here the synthesis of a library of indole-3-glyoxylamides and their evaluation as potential antiprion agents. A number of compounds demonstrated submicromolar activity in a cell line model of prion disease together with a defined structure-activity relationship, permitting the design of more potent compounds that effected clearance of scrapie in the low nanomolar range. Thus, the indole-3-glyoxylamides described herein constitute ideal candidates to progress to further development as potential therapeutics for the family of human prion disorders. 2009 American Chemical Society.
- Thompson, Mark J.,Borsenberger, Vinciane,Louth, Jennifer C.,Judd, Katie E.,Chen, Beining
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experimental part
p. 7503 - 7511
(2010/06/11)
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- NOVEL SULPHOXIMINE-SUBSTITUTED QUINAZOLINE AND QUINAZOLINE DERIVATIVES AS KINASE INHIBITORS
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The present invention relates to a quinoline or quinazoline derivative having the general formula (A): in which R3, R4, W, Y and Q are indicated in the description and the claims, the use of the compounds of the general formula (A) f
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Page/Page column 30
(2009/01/20)
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- Kinase inhibitors
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The present invention provides a method for identifying inhibitors of protein kinases. Methods are also provided for inhibiting protein kinase activity. Specific non-peptide protein tyrosine kinase inhibitors are provided. The protein kinases produced usi
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Page/Page column 23
(2010/11/08)
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- Synthesis and photochemical properties of a new water-soluble coumarin, designed as a chromophore for highly water-soluble and photolabile protecting group
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The absorption spectra and fluorescence spectra of a coumarin derivative (1), designed to be a water-soluble photolabile protecting group for caged compounds, were successfully observed in aqueous buffer solutions at pH 2.0-12.5 for the first time. Coumar
- Senda, Naoko,Momotake, Atsuya,Nishimura, Yoshinobu,Arai, Tatsuo
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p. 1753 - 1757
(2007/10/03)
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- Design, synthesis and evaluation of potential inhibitors of HIV gp120-CD4 interactions
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This paper describes an approach to prevent HIV-cell fusion by disrupting the interaction between HIV protein gp120 and CD4 receptor. The CD4 residues Phe43 and Arg59 make important interactions with gp120. Small molecule analogues were made to mimic the crucial features of these residues. The analogues were assayed using a cellular 'FIGS' assay to measure inhibition of cell fusion and caused some inhibition.
- Boussard, Cyrille,Klimkait, Thomas,Mahmood, Naheed,Pritchard, Martin,Gilbert, Ian H.
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p. 2673 - 2676
(2007/10/03)
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- Diazinopyrimidines
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The present invention provides a compound of the formula: or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, X1, X2, and Ar1 are as defined herein. The present invention als
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Page/Page column 23
(2008/06/13)
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- Synthesis of substituted oxindoles from α-chloroacetanilides via palladium-catalyzed C - H functionalization
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A novel method for the synthesis of oxindoles is described. In the presence of catalytic palladium acetate and 2-(di-tert-butylphosphino)biphenyl, α-chloroacetanilides are converted to oxindoles in good to excellent yields with high functional group compatibility using triethylamine as a stoichiometric base. The cyclization is highly regioselective, obviating the need for prefunctionalized arenes. Plausible mechanistic pathways for the reaction are discussed. Copyright
- Hennessy, Edward J.,Buchwald, Stephen L.
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p. 12084 - 12085
(2007/10/03)
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- The design, synthesis and activity of non-ATP competitive inhibitors of pp60(c-src) tyrosine kinase. Part 1: Hydroxynaphthalene derivatives
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A series of hydroxynaphthalene pp60(c-src) non-peptide inhibitors was designed, using the crystal structure of the insulin receptor tyrosine kinase as a qualitative model, to target the peptide substrate binding site. Representative inhibitors were shown to bind non-competitively with respect to ATP. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Marsilje, Thomas H.,Milkiewicz, Karen L.,Hangauer, David G.
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p. 477 - 481
(2007/10/03)
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- Synthesis and protein tyrosine phosphatase inhibitory activity of dephostatin analogs
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We have synthesized derivatives of dephostatin, a protein tyrosine phosphatase (PTPase) inhibitor, to study the structure-activity relationships of this inhibitor. Inactive analogs revealed some insight into structural requirements for PTPase inhibitory activity of dephostatin. Both a nitroso group and phenolic hydroxyl groups were found to be essential for the inhibitory activity. Among the dephostatin derivatives synthesized, one of the regioisomers of dephostatin showed PTPase inhibitory activity equivalent to that of dephostatin, and also had increased stability.
- Watanabe,Takeuchi,Otsuka,Tanaka,Umezawa
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p. 1460 - 1466
(2007/10/03)
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- Photocyclization of aryl enaminones. An efficient route to indole alkaloid synthons
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The photocyclization of enaminones was extended to aryl enaminones bearing a substituent on the aromatic moiety.This reaction was studied in order to achieve the synthesis of indole alkaloid synthons.Trials of regioselectivity control were made by using g
- Gardette, Daniel,Gramain, Jean-Claude,Lepage, Marie-Eve,Troin, Yves
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p. 213 - 219
(2007/10/02)
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