- Flexible Analogues of Azaindole DYRK1A Inhibitors Elicit Cytotoxicity in Glioblastoma Cells
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DYRK1A is a novel target for epidermal growth factor receptor (EGFR)-dependent glioblastoma and it represents a promising strategy for cancer therapy. DYRK1A inhibition has been found to promote EGFR degradation in glioblastoma cells by triggering endocyt
- Zhou, Qingqing,Reekie, Tristan A.,Abbassi, Ramzi H.,Venkata, Dinesh Indurthi,Font, Josep S.,Ryan, Renae M.,Rendina, Louis M.,Munoz, Lenka,Kassiou, Michael
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Read Online
- Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors
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CYP121 of Mycobacterium tuberculosis (Mtb) is an essential target for the development of novel potent drugs against tuberculosis (TB). Besides known antifungal azoles, further compounds of the azole class were recently identified as CYP121 inhibitors with
- Walter, Isabell,Adam, Sebastian,Gentilini, Maria Virginia,Kany, Andreas M.,Brengel, Christian,Thomann, Andreas,Sparwasser, Tim,K?hnke, Jesko,Hartmann, Rolf W.
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p. 2786 - 2801
(2021/06/27)
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- Polymerizable compounds. Liquid crystal composition and liquid crystal display device
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A polymerizable compound having a formula of formula (I): Ring A, ring B, Z1 , Z2 , R, P, n And m are as described in the specification and the application patent range, respectively. The liquid crystal composition containing the pol
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Paragraph 0079; 0081
(2021/09/08)
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- CHEMILUMINESCENT IMIDAZOPYRAZINONE-BASED PHOTOSENSITIZERS WITH AVAILABLE SINGLET AND TRIPLET EXCITED STATES
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The present application describes the development of novel photosensitizers that can undergo self-excitation due to a chemiluminescent reaction, to produce readily-available singlet and/or triplet states and are composed by an imidazopyrazinone core. This core is functionalized with a variety of chromophores and spin converters, allowing to modulate the optical and photosensitizing properties. In one application, the chemiluminescent reaction is triggered by the superoxide anion, overexpressed in tumors, and by molecular oxygen, in aprotic solvents. The photosensitizers can be used in photodynamic therapy of cancer, without the need for external light sources and when triggered by a tumor marker, superoxide anion, while eliminating the restrictions of this therapy associated with tumor size and localization. The emission of light during the self-excitation reaction, and the resulting non-autofluorescence and low background noise, allow their use in tumor diagnostics. The photosensitizers can also be used without light sources and metal elements in photocatalysis reactions.
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Page/Page column 29
(2019/11/19)
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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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- COELENTERAZINE ANALOGUES AND COELENTERAMIDE ANALOGUES
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Coelenterazine analogs with different luminescence properties from conventional ones and coelenteramide analogs with different fluorescence properties from conventional ones have been desired. The invention provides coelenterazine analogs modified at the
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Paragraph 0249; 0250
(2014/10/29)
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- Synthesis of macrocyclic ketones exploiting palladium-catalyzed activation of carboxylic acids as an enabling step
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The novel synthesis of macrocyclic arylketones via palladium-catalyzed cross-coupling of arylboronic acids and carboxylic acids, activated by the treatment with di(N-succinimidyl) carbonate, is disclosed. This allows the high yielding synthesis of various
- Kapdi, Anant R.,Fairlamb, Ian J. S.
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p. 961 - 964
(2013/06/27)
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- Design of a highly selective and potent class of non-planar estrogen receptorβ agonists
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Selective activation of the estrogen receptorβ (ERβ) could be a safe approach to hormone replacement therapy for both women and men, in contrast to the estrogens currently used for women which activate both ERβ and ERα, occasionally causing severe side effects. The selective ERβ agonist AC-131 has shown efficacy in animal models of Parkinson's disease and neuropathic pain. With the use of AC-131 as template, herein we report the discovery, synthesis, and structure-activity relationship (SAR) study of a new class of dihydrobenzofurans as potent and selective ERβ agonists. The SAR was established by enantioselective synthesis, molecular modeling, and whole-cell-based functional assays. The most potent diastereomer, cis-10-SR, was shown to have an EC50 value of A T-shaped trans-SS diastereomer of 4-{3-fluoro-8-oxatricyclo[7.5.0.02,7]tetradeca-2,4,6-trien-1-yl}phenol (10) was found to be 1000-fold selective for ERβ over ERα.
- Sunden, Henrik,Ma, Jian-Nong,Hansen, Lars K.,Gustavsson, Anna-Lena,Burstein, Ethan S.,Olsson, Roger
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supporting information
p. 1283 - 1294
(2013/08/23)
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- COELENTERAZINE ANALOGUES AND COELENTERAMIDE ANALOGUES
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Coelenterazine analogues with different luminescence properties from conventional ones and coelenteramide analogues with different fluorescence properties from conventional ones have been desired. The invention provides coelenterazine analogues modified at the 8-position of coelenterazine and coelenteramide analogues modified at the 2- or 3-position of coelenteramide.
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- SUBSTITUTED SPIROKETAL DERIVATIVES AND USE THEREOF AS THERAPEUTIC DRUG FOR DIABETES
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The present invention provides a compound represented by Formula (II): wherein R1 is a chlorine atom, a fluorine atom, a methyl group or an ethynyl group; Ar is a group represented by the following Formula (a), Formula (b), Formula (c) or Formula (d): wherein R2 is a C1-6 alkyl group which may be substituted with one or more halogen atoms, a C1-6 alkoxy group which may be substituted with one or more halogen atoms, a C1-3 alkylthio group, a halogen atom, a C1-3 alkylcarbonyl group or a C2-5 alkynyl group which may be substituted with —OR4; R3 is a hydrogen atom or a C1-3 alkyl group; R4 is a hydrogen atom or a C1-3 alkyl group; provided that Ar is a group represented by Formula (a) when R1 is a fluorine atom, methyl group or an ethynyl group, and that R2 is methoxy group, an ethoxy group, an isopropyl group, a propyl group, a trifluoromethyl group, a trifluoromethoxy group, 2-fluoroethyl group or 1-propynyl group when R1 is a methyl group or a pharmaceutically acceptable salt or a solvate thereof and a pharmaceutical agent, a pharmaceutical composition and so on comprising the compound.
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Page/Page column 35
(2011/11/13)
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- Addition of arylboronic acids to arylpropargyl alcohols en route to indenes and quinolines
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A regio- and stereoselective rhodium-catalyzed synthesis of trisubstituted allylic alcohols is described. The utility of these synthons is demonstrated in a convenient synthesis of indenes and quinolines.
- Panteleev, Jane,Huang, Richard Y.,Lui, Erica K. J.,Lautens, Mark
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supporting information; experimental part
p. 5314 - 5317
(2011/12/01)
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- Locked chromophore analogs reveal that photoactive yellow protein regulates biofilm formation in the deep sea bacterium Idiomarina loihiensis
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Idiomarina loihiensis is a heterotrophic deep sea bacterium with no known photobiology. We show that light suppresses biofilm formation in this organism. The genome of I. loihiensis encodes a single photoreceptor protein: a homologue of photoactive yellow
- Van Der Horst, Michael A.,Stalcup, T. Page,Kaledhonkar, Sandip,Kumauchi, Masato,Hara, Miwa,Xie, Aihua,Hellingwerf, Klaas J.,Hoff, Wouter D.
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supporting information; experimental part
p. 17443 - 17451
(2010/03/25)
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- HSP90 INHIBITORS CONTAINING A ZINC BINDING MOIETY
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The present invention relates to HSP90 inhibitors containing a zinc binding moiety and their use in the treatment of cell proliferative diseases such as cancer. The said derivatives may further act as HDAC inhibitors.
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Page/Page column 29; 35
(2009/04/24)
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- SUBSTITUTED SPIROKETAL DERIVATIVE AND USE THEREOF AS DRUG FOR TREATING DIABETES
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The present invention provides a compound represented by Formula (II): wherein R1 is a chlorine atom, a fluorine atom, a methyl group or an ethynyl group; Ar is a group represented by the following Formula (a), Formula (b), Formula (c) or Formula (d): wherein R2 is a C1-6 alkyl group which may be substituted with one or more halogen atoms, a C1-6 alkoxy group which may be substituted with one or more halogen atoms, a C1-3 alkylthio group, a halogen atom, a C1-3 alkylcarbonyl group or a C2-5 alkynyl group which may be substituted with -OR4; R3 is a hydrogen atom or a C1-3 alkyl group; R4 is a hydrogen atom or a C1-3 alkyl group; provided that Ar is a group represented by Formula (a) when R1 is a fluorine atom, methyl group or an ethynyl group, and that R2 is methoxy group, an ethoxy group, an isopropyl group, a propyl group, a trifluoromethyl group, a trifluoromethoxy group, 2-fluoroethyl group or 1-propynyl group when R1 is a methyl group or a pharmaceutically acceptable salt or a solvate thereof and a pharmaceutical agent, a pharmaceutical composition and so on comprising the compound.
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Page/Page column 46
(2009/05/29)
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- ERβ ligands. Part 2: Synthesis and structure-activity relationships of a series of 4-hydroxy-biphenyl-carbaldehyde oxime derivatives
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A series of biphenyl carbaldehyde oximes (6) was prepared and shown to have significant selectivity for the estrogen receptor-β (ERβ). The exploitation of the oxime moiety as a hydrogen bond donating group, which mimicked the C-ring of genistein makes these compounds unique. Molecular modeling studies showed the oxime moiety hydrogen bonding to the histidine residue, which was supported by the structure-activity relationships. The most potent compounds in this study had IC50 values in a radioligand binding assay of between 8-35nM. Among the most selective compounds were 6i and 6s (49- and 31-fold ERβ selective, respectively).
- Yang, Cuijian,Edsall Jr., Richard,Harris, Heather A.,Zhang, Xiaochun,Manas, Eric S.,Mewshaw, Richard E.
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p. 2553 - 2570
(2007/10/03)
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- HYDROXY-BIPHENYL-CARBALDEHYDE OXIME DERIVATIVES AND THEIR USE AS ESTROGENIC AGENTS
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This invention provides estrogen receptor modulators having the structure formula (I): wherein R1 to R6 and R8 are as defined in the specification; or a pharmaceutically acceptable salt thereof.
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- A new class of potent non-imidazole H3 antagonists: 2-Aminoethylbenzofurans
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2-Aminoethylbenzofurans constitute a new class of H3 antagonists that are more rotationally constrained than most previously reported H3 antagonists. They retain high potency at human and rat receptors, with efficient CNS penetration observed in 35. The SAR of the basic amine moiety was compared in three different series of analogues. The greatest potency was found in analogues bearing a 2-methylpyrrolidine, a 2,5-dimethylpyrrolidine, or a 2,6-dimethylpiperidine.
- Cowart, Marlon,Pratt, John K.,Stewart, Andrew O.,Bennani, Youssef L.,Esbenshade, Timothy A.,Hancock, Arthur A.
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p. 689 - 693
(2007/10/03)
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- Pyridine compounds and their pharmaceutical use
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A compound of formula (I) wherein each symbol is as defined in the specification, and pharmaceutically acceptable salts thereof. The compound (I) of the present invention and pharmaceutically acceptable salts thereof possess a strong inhibitory activity on the production of nitric oxide (NO), and are useful for prevention and/or treatment of NOS(nitric oxide synthasey)-mediated diseases such as adult respiratory distress syndrome, myocarditis, synovitis, septic shock, insulin-ependent diabetes mellitus, ulcerative colitis, cerebral infarction, rheumatoid arthritis, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, pain, ulcer, and the like in human being and animals.
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- N-(alkyl)-2-amino-1,4-pyrazine derivatives: Synthesis and antioxidative properties of 3- and 3,5-p-hydroxyphenyl-substituted compounds
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2-Amino-5-(p-hydroxyphenyl)-1,4-pyrazine and 2-amino-3,5-bis(p-hydroxyphenyl)-1,4-pyrazine are endowed with excellent antioxidative properties. For a possible development in medicinal chemistry, the lipophilicity of these lead compounds has to be increased. Therefore various methods of N-alkylation were systematically explored. The best results were obtained by quenching aminopyrazinyl anion with alkyl iodides, and by coupling aldehydes (reductive amination) in the presence of phenylsilane and tin catalyst. Aminopyrazines equipped with linear alkyl side-chains of at least six carbons showed improved radical-scavenging properties in lipidic media.
- Jeanjot, Paul,Bruyneel, Fre?de?ric,Arrault, Axelle,Gharbi, Sonia,Cavalier, Jean-Franc?ois,Abels, Agne?s,Marchand, Ce?cile,Touillaux, Roland,Rees, Jean-Franc?ois,Marchand-Brynaert, Jacqueline
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p. 513 - 522
(2007/10/03)
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- N-HYDROXYFORMAMIDE DERIVATIVES AS INHIBITORS OF MATRIX METALLOPROTEINASES
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Compounds having formula (I) are matrix metalloproteinase inhibitors. Also disclosed are matrix metalloproteinase-inhibiting compositions and methods of inhibiting matrix metalloproteinase in a mammal.
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- From peptides to non-peptide peptidomimetics: design and synthesis of new piperidine inhibitors of aspartic peptidases.
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[reaction: see text] The 3-alkoxy-4-arylpiperidine inhibitors of aspartic peptidases are shown to be a new type of non-peptide peptidomimetic inhibitor. These piperidines can be designed from peptide-derived inhibitors by use of a structure-generating pro
- Bursavich,West,Rich
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p. 2317 - 2320
(2007/10/03)
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- REVERSE HYDROXAMATE INHIBITORS OF MATRIX METALLOPROTEINASES
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Compounds having the formula are matrix metalloproteinase inhibitors. Also disclosed are matrix metalloproteinase-inhibiting compositions and methods of inhibiting matrix metalloproteinase in a mammal.
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- Reverse hydroxamate inhibitors of matrix metalloproteinases
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Compounds having the formula are matrix metalloproteinase inhibitors. Also disclosed are matrix metalloproteinase-inhibiting compositions and methods of inhibiting matrix metalloproteinase in a mammal.
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- Discovery of potent nonpeptide inhibitors of stromelysin using SAR by NMR
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With the use of an NMR-based method, potent (IC50 25 nM) nonpeptide inhibitors of the matrix metalloproteinase stromelysin (MMP-3) were discovered. The method, called SAR by NMR (for structure-activity relationships by nuclear magnetic resonance), involves the identification, optimization, and linking of compounds that bind to proximal sites on a protein. Using this technique, two ligands that bind weakly to stromelysin (acetohydroxamic acid, K(D) = 17 mM; 3-(cyanomethyl)-4'-hydroxybiphenyl, K(D) = 0.02 mM) were identified. On the basis of NMR-derived structural information, the two fragments were connected to produce a 15 nM inhibitor of this enzyme. This compound was rapidly discovered (less than 6 months) and required only a minimal amount of chemical synthesis. These studies indicate that the SAR by NMR method can be effectively applied to enzymes to yield potent lead inhibitors-an important part of the drug discovery process.
- Hajduk,Sheppard,Nettesheim,Olejniczak,Shuker,Meadows,Steinman,Carrera Jr.,Marcotte,Severin,Walter,Smith,Gubbins,Simmer,Holzman,Morgan,Davidsen,Summers,Fesik
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p. 5818 - 5827
(2007/10/03)
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