- First total synthesis of β-carboline alkaloid trigonostemine G and its derivatives
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The β-carboline core is the base structure of several biologically active natural and unnatural compounds. Herein, we report the first total synthesis of trigonostemine G, which is a newly isolated natural β-carboline alkaloid from the twigs of Trigonostemon filipes. Synthesis of two structurally close derivatives of trigonostemine G is also reported. Key step of the syntheses involves a nucleophilic addition of 5-{[tert-butyl(dimethyl) silyl]oxy}-1H-indole to 1-formyl-β-carboline building blocks.
- Szabó, Tímea,Dancsó, András,Volk, Balázs,Milen, Mátyás
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Read Online
- Discovery of a Class of Potent and Selective Non-competitive Sentrin-Specific Protease 1 Inhibitors
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Sentrin-specific proteases (SENPs) are responsible for the maturation of small ubiquitin-like modifiers (SUMOs) and the deconjugation of SUMOs from their substrate proteins. Studies on prostate cancer revealed an overexpression of SENP1, which promotes prostate cancer progression as well as metastasis. Therefore, SENP1 has been identified as a novel drug target against prostate cancer. Herein, we report the discovery and biological evaluation of potent and selective SENP1 inhibitors. A structure-activity relationship (SAR) of the newly identified pyridone scaffold revealed allosteric inhibitors with very attractive in vitro ADMET properties regarding plasma binding and plasma stability for this challenging target. This study also emphasizes the importance of biochemical mode of inhibition studies for de novo designed inhibitors.
- Brand, Michael,Frasson, David,Gall, Flavio,Hunziker, Lukas,Kroslakova, Ivana,Lindenmann, Urs,Riedl, Rainer,Sievers, Martin
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- Partially fluorinated alkoxy groups ? Conformational adaptors to changing environments
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Lipophilicities of partially fluorinated n-propyloxy indole derivatives and their rates of oxidative metabolic degradation are presented. Comparison of the lipophilicity data with those of compounds containing the same partially fluorinated propyl groups attached to carbon or nitrogen reveals remarkable similarities and some distinct differences. A further striking difference in lipophilicity pattern is noted between terminally fluorinated n-propyloxy and corresponding methoxy derivatives. The lipophilicity patterns are rationalized in a consistent way by application of a simple rule-of-thumb based on polar-bond vector superposition, taking into account conformational aspects deduced from X-ray crystal structures and quantum chemical calculations. Several of these groups can switch between polar and non-polar conformations of comparable energies and may thus be regarded as potentially effective conformational adaptors to changing chemical environments. All compounds exhibit relatively high rates of metabolic degradation with a moderate correlation between degradation rate and lipophilicity.
- Huchet, Quentin A.,Trapp, Nils,Kuhn, Bernd,Wagner, Bj?rn,Fischer, Holger,Kratochwil, Nicole A.,Carreira, Erick M.,Müller, Klaus
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- Total synthesis of (±)-hyrtiazepine
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The total synthesis of the azepinoindole alkaloid, (±)-hyrtiazepine, was achieved. Construction of the azepinoindole core structure was carried out by C-4 selective α-hydroxyalkylation of 5-hydroxyindole, introduction of serine at C-3 of the indole moiety, and intramolecular imination.
- Ito, Fumihiro,Shudo, Koichi,Yamaguchi, Kentaro
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experimental part
p. 1805 - 1811
(2011/04/16)
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- Nucleoside Aryl Phosphoramidates for the Treatment of RNA-Dependent RNA Viral Infection
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The present invention provides nucleoside aryl phosphoramidates of structural formula (I) which are precursors to inhibitors of RNA-dependent RNA viral polymerase. These compounds are precursors to inhibitors of RNA-dependent RNA viral replication and are
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Page/Page column 21
(2010/09/18)
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- JAK INHIBITOR
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A JAK inhibitor comprising, as an active ingredient, a nitrogen-containing heterocyclic compound represented by formula (I) {wherein W represents a nitrogen atom or -CH-; X represents -C (=O) - or -CHR4- (wherein R4 represents a hydrogen atom, or the like); R1 represents the formula described below [wherein Q1 represents-CR8-(wherein R8 represents a hydrogen atom, substituted or unsubstituted lower alkyl, or the like); Q2 represents -NR15- (wherein R15 represents a hydrogen atom, substituted or unsubstituted lower alkyl, or the like); and R5 and R6 may be the same or different and each represents a hydrogen atom, halogen, carboxy, substituted or unsubstituted lower alkyl, or the like], or the like; and R2 and R3 may be the same or different and each represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, or the like} or a pharmaceutically acceptable salt thereof.
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Page/Page column 82
(2009/10/21)
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- Indole derivatives comprising an acetylene group
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This invention is directed to compounds of the formula (I): wherein one of R6, R7, R8 and R9 is and X, R1 to R12, m, n and o are as defined in the description, and pharmaceutically acceptable salts and/or esters thereof. The invention is also directed to pharmaceutical compositions containing such compounds, to a process for their preparation and to their use for the treatment and/or prevention of diseases which are modulated by PPARδ and/or PPARα agonists.
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Page/Page column 23
(2008/06/13)
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- Indolyl and dihydroindolyl derivatives, their manufacture and use as pharmaceutical agents
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This invention relates to compounds of the formula wherein one of R6, R7 and R8 is and X, Y1 to Y4, R1 to R14 and n are as defined in the description, and to all enantiomers and pharmaceutically acceptable salts and/or esters thereof The invention further relates to pharmaceutical compositions containing such compounds, to a process for their preparation and to their use for the treatment and/or prevention of diseases which are modulated by PPARδ and/or PPARα agonists.
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Page/Page column 20
(2008/06/13)
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- Thiazolyl-indole derivatives, their manufacture and use as pharmaceutical agents
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This invention relates to compounds of the formula wherein one of R6, R7 or R8 is and all enantiomers and pharmaceutically acceptable salts and/or esters thereof as well as pharmaceutical compositions containing such compo
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- Indolyl derivatives
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This invention relates to compounds of the formula I: wherein one of R6, R7 and R8 is and R1 to R15 and n are as defined in the description, and all enantiomers and pharmaceutically acceptable salts a
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Page/Page column 22
(2010/02/14)
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- THERAPEUTIC AGENTS I
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Compounds of formula(I), processes for preparing such compounds, their use in the treatment of obesity, psychiatric disorders, cognitive disorders, memory disorders, schizophrenia, epilepsy, and related conditions, and neurological disorders such as dementia, multiple sclerosis, Parkinson's disease, Huntington's chorea and Alzheimer's disease and pain related disorders, and pharmaceutical compositions containing them.
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Page/Page column 72
(2010/02/12)
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- INDOLYL PYRAZINONE DERIVATIVES USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS AND DISEASES ASSOCIATED WITH ANGIOGENESIS
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This invention relates to a compound of Formula I (I)and its use in treating hyper-proliferative disorders and diseases associated with angiogenesis.
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- Orally active salts with tyrosine kinase activity
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The present invention relates to orally active salts of compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angio-genesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like in mammals.
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- Tyrosine kinase inhibitors
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The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like in mammals.
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