- Hypoiodite-Catalyzed Chemoselective Tandem Oxidation of Homotryptamines to Peroxy- And Epoxytetrahydropyridoindolenines
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We developed the hypoiodite-catalyzed tandem dearomative peroxycyclization of homotryptamine derivatives to peroxytetrahydropyridoindolenines under mild conditions. During the course of a mechanistic study, we found that a tandem oxidative cyclization/epoxidation as an unexpected reaction proceeded in the presence of TEMPO as an additive. Intramolecular oxidative aminocyclization of homotryptamines at the C-2 position would give tetrahydropyridoindole, a common intermediate for both reactions. Control experiments suggested that while oxidative coupling with TBHP at the C-3 position might afford peroxyindolenines, a preferential electrophilic addition of TEMPO+, which might be generated in situ by the hypoiodite-catalyzed oxidation of TEMPO, at C-3 position followed by elimination and epoxidation might give epoxyindolenines. This serendipitous finding prompted us to develop a chemoselective divergent synthesis of peroxy- and epoxyindolenines by simple modification of the reaction conditions.
- Uyanik, Muhammet,Tanaka, Hiroki,Ishihara, Kazuaki
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supporting information
p. 8049 - 8054
(2020/11/02)
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- Synthesis and Biological Evaluation of Derivatives of Indoline as Highly Potent Antioxidant and Anti-inflammatory Agents
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We describe the preparation and evaluation of novel indoline derivatives with potent antioxidant and anti-inflammatory activities for the treatment of pathological conditions associated with chronic inflammation. The indolines are substituted at position 1 with chains carrying amino, ester, amide, or alcohol groups, and some have additional substituents, Cl, MeO, Me, F, HO, or BnO, on the benzo ring. Concentrations of 1 pM to 1 nM of several compounds protected RAW264.7 macrophages against H2O2 induced cytotoxicity and LPS induced elevation of NO, TNF-α, and IL-6. Several derivatives had anti-inflammatory activity at 1/100th of the concentration of unsubstituted indoline. Four compounds with ester, amine, amide, or alcohol side chains injected subcutaneously in mice at a dose of 1 μmol/kg or less, like dexamethasone (5.6 μmol/kg) prevented LPS-induced cytokine elevation in the brain and peripheral tissues. Subcutaneous injection of 100 μmol/kg of these compounds caused no noticeable adverse effects in mice during 3 days of observation.
- Zeeli, Shani,Weill, Tehilla,Finkin-Groner, Efrat,Bejar, Corina,Melamed, Michal,Furman, Svetlana,Zhenin, Michael,Nudelman, Abraham,Weinstock, Marta
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supporting information
p. 4004 - 4019
(2018/05/07)
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- INDOLINE DERIVATIVES, COMPOSITIONS COMPRISING THEM AND USES THEREOF
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The present invention is directed to indoline derivatives and salts thereof, compositions comprising them and uses thereof for the treatment of diseases and disorders associated with at least one of oxidative stress, an immune response, release of NO and release of pro-inflammatory cytokine.
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Page/Page column 60
(2017/09/24)
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- Screening of NOS activity and selectivity of newly synthesized acetamidines using RP-HPLC
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Nitric Oxide Synthase (NOS) inhibitors could play a powerful role in inflammatory and neurodegenerative diseases. In this work, novel acetamidine derivatives of NOS were synthesized and the inhibitor activity was evalued. To screen the activity and selectivity, the l-citrulline residue, after the enzymatic NOS assay, was derivatized with o-phthaldialdehyde/N-acetyl cysteine (OPA/NAC) and then evaluated by RP-HPLC method with fluorescence detection.All compounds did not affect the activity of endothelial and neuronal isoforms, while nine of them possessed a percentage of iNOS activity at 10 μM lower than 50%, and were selected for IC50 evaluation. Among them, a compound emerged as a very potent (IC50 of 53 nM) and selective iNOS inhibitor.
- Fantacuzzi, Marialuigia,Maccallini, Cristina,Di Matteo, Mauro,Ammazzalorso, Alessandra,Bruno, Isabella,De Filippis, Barbara,Giampietro, Letizia,Mollica, Adriano,Amoroso, Rosa
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p. 419 - 424
(2016/02/16)
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- Highly active modulators of indole signaling alter pathogenic behaviors in gram-negative and gram-positive bacteria
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Indole is a universal signal that regulates various bacterial behaviors, such as biofilm formation and antibiotic resistance. To generate mechanistic probes of indole signaling and control indole-mediated pathogenic phenotypes in both Gram-positive and Gram-negative bacteria, we have investigated the use of desformylflustrabromine (dFBr) derivatives to generate highly active indole mimetics. We have developed non-microbicidal dFBr derivatives that are 27-2000 times more active than indole in modulating biofilm formation, motility, acid resistance, and antibiotic resistance. The activity of these analogues parallels indole, because they are dependent on temperature, the enzyme tryptophanase TnaA, and the transcriptional regulator SdiA. This investigation demonstrates that molecules based on the dFBr scaffold can alter pathogenic behaviors by mimicking indole-signaling pathways. Phenotype control: Non-microbicidal desformylflustrabromine (dFBr) derivatives that are 27-2000 times more active than indole in modulating biofilm formation, motility, acid resistance, and antibiotic resistance were developed. This investigation demonstrates that molecules based on the dFBr scaffold can alter pathogenic behaviors by mimicking indole-signaling pathways (see scheme).
- Minvielle, Marine J.,Eguren, Kristen,Melander, Christian
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p. 17595 - 17602
(2014/01/06)
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- ORGANIC COMPOUNDS
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The invention relates to organic compounds which have interesting pharmaceutical properties. In particular, the compounds are useful in the treatment and/or prevention of infections such as those caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, Trypanosoma cruzi and parasites of the Leishmania genus such as, for example, Leishmania donovani. The invention also relates to pharmaceutical compositions containing the compounds, as well as processes for their preparation.
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Page/Page column 12; 16
(2009/12/02)
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- Enantioselective electrophilic amination of α-cyanothioacetates with azodicarboxylates catalyzed by an axially chiral guanidine base
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An enantioselective electrophilic amination of α-substituted cyanothioacetates with azodicarboxylate is demonstrated using an axially chiral guanidine as a chiral Bronsted base catalyst. The corresponding product, having a quaternary stereogenie center at
- Terada, Masahiro,Tsushima, Daisuke,Nakano, Megumi
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supporting information; experimental part
p. 2817 - 2821
(2010/03/05)
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- Binding of serotonin to the human serotonin transporter. Molecular modeling and experimental validation
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Molecular modeling and structure-activity relationship studies were performed to propose a model for binding of the neurotransmitter serotonin (5-HT) to the human serotonin transporter (hSERT). Homology models were constructed using the crystal structure of a bacterial homologue, the leucine transporter from Aquifex aeolicus, as the template and three slightly different sequence alignments. Induced fit docking of 5-HT into hSERT homology models resulted in two different binding modes. Both show a salt bridge between Asp98 and the charged primary amine of 5-HT, and both have the 5-HT C6 position of the indole ring pointing toward Ala173. The difference between the two orientations of 5-HT is an enantiofacial discrimination of the indole ring, resulting in the 5-hydroxyl group of 5-HT being vicinal to either Ser438/Thr439 or Ala169/Ile172/Ala173. To assess the binding experimentally, binding affinities for 5-HT and 17 analogues toward wild type and 13 single point mutants of hSERT were measured using an approach termed paired mutant-ligand analogue complementation (PaMLAC). The proposed ligand-protein interaction was systematically examined by disrupting it through site-directed mutagenesis and reestablishing another interaction via a ligand analogue matching the mutated residue, thereby minimizing the risk of identifying indirect effects. The interactions between Asp98 and the primary amine of 5-HT and the interaction between the C6-position of 5-HT and hSERT position 173 was confirmed using PaMLAC. The measured binding affinities of various mutants and 5-HT analogues allowed for a distinction between the two proposed binding modes of 5-HT and biochemically support the model for 5-HT binding in hSERT where the 5-hydroxyl group is in close proximity to Thr439.
- Celik, Leyla,Sinning, Steffen,Severinsen, Kasper,Hansen, Carsten G.,Moller, Maria S.,Bols, Mikael,Wiborg, Ove,Schiott, Birgit
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p. 3853 - 3865
(2008/12/20)
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- Indole-3-propionamide and derivatives thereof
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Indolepropionamide (IPAM) and related compounds, pharmaceutical or dietary compositions thereof and methods of using said compounds are disclosed for use as a preventative or therapeutic treatment for many conditions related to oxidative damage. Oxidative damage increases in aging and age related disorders and is widespread in many neurodegenerative conditions including Alzheimer's disease, Parkinson's disease and others. Indolepropionamide is a potent anti-oxidant and anti-aging molecule, with superior properties as compares to previously known compounds.
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Page/Page column 4
(2008/06/13)
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- Toward the control of Leptosphaeria maculans: Design, syntheses, biological activity, and metabolism of potential detoxification inhibitors of the crucifer phytoalexin brassinin
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Brassinin (1), a crucial plant defense produced by crucifers, is detoxified by the phytopathogenic fungus Leptosphaeria maculans (Phoma lingam) to indole-3-carboxaldehyde using a putative brassinin oxidase. Potential inhibitors of brassinin detoxification
- Pedras, M. Soledade C.,Jha, Mukund
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p. 4958 - 4979
(2007/10/03)
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- Studies toward the discovery of the next generation of antidepressants. 3. Dual 5-HT1A and serotonin transporter affinity within a class of N-aryloxyethylindolylalkylamines
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N-Aryloxylethylindolealkylamines (5) having dual 5-HT transporter and 5-HT1A affinity are described. These compounds represent truncated analogues of our previously reported piperidinyl derivatives (3). Compounds in this investigation were found to have more similar affinities and functional activities for the 5-HT1A receptor and 5-HT transporter. Though 5-HT1A antagonism is not consistently observed throughout series 5, several molecular features were found to be essential to obtain high and balanced activities. The proper placement of a heteroatom in the aryl ring and the length of the linkage used to tether the indole moiety had significant influence on 5-HT1A and 5-HT transporter affinities. Introduction of a halogen into the aryl ring usually lowered intrinsic activity and in some cases led to full 5-HT1A antagonists. Compounds 33 and 34 were observed to be full 5-HT1A antagonists with Ki values of approximately 30 nM for the 5-HT1A receptor and Ki values of 5 and 0.5 nM for the 5-HT transporter, respectively. Unfortunately, similar to our previous series (3), compounds in this report also had high affinity for the α1 receptor.
- Mewshaw, Richard E.,Zhou, Dahui,Zhou, Ping,Shi, Xiaojie,Hornby, Geoffrey,Spangler, Taylor,Scerni, Rosemary,Smith, Deborah,Schechter, Lee E.,Andree, Terrance H.
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p. 3823 - 3842
(2007/10/03)
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- Intramolecular Mannich reaction of 2-oxotryptamine and homologues with oxo reagents yielding spiro compounds. Part II
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2-Oxotryptamine and its homo derivative undergo intramolecular Mannich-type cyclization with acetone and other ketones to give spiro[indole-3,3′-pyrrolidin]-2-ones and spiro[indole-3,3′-piperidin]-2-ones. A similar reaction with the bis-homologue of 2-oxotryptamine to yield spiro[azepane-3,3′-indol]-2′-ones was unsuccessful.
- Doernyei, Gabor,Incze, Maria,Kajtar-Peredy, Maria,Szantay, Csaba
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p. 1669 - 1680
(2007/10/03)
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- Tyrosine Kinase Inhibitors. 2. Synthesis of 2,2'-Dithiobis(iH-indole-3-alkanamides) and Investigation of Their Inhibitory Activity against Epidermal Growth Factor Receptor and pp60v-src Protein Tyrosine Kinases
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A series of amide analogues of the 2,2'-dithiobis(1H-indole-3-alkanoic acid) class of tyrosine kinase inhibitors have been prepared, by reaction of 1H-indole-3-alkanamides (8) with S2Cl2, and separation of the desired disulfides from the initial mixtures of mono-, di-, and trisulfides formed. These amides were evaluated in vitro against epidermal growth factor receptor and pp60v-src protein tyrosine kinases. Inhibitory activity against EGF receptor tyrosine kinase was chain-length dependent, with the propanamides being the most effective. Hydrogen bond donor capabilities in the amide function did not appear to be necessary, with an N-benzylamide being the most potent (IC50 = 0.85 μM). Further substitution on the benzyl ring did not increase potency, and substitution in the α-position of the propanamide side chain was acceptable. A water-soluble α-NH2 derivative showed good inhibitory activity toward the enzyme, was a potent inhibitor of cell growth in fibroblasts, and selectively inhibited intracellular tyrosine phosphorylation patterns. The nonreceptor kinase pp60v-src was in general much more sensitive than EGF receptor kinase to inhibition by these compounds, but with less pronounced structure-activity relationships.
- Thompson, Andrew M.,Fry, David W.,Kraker, Alan J.,Denny, William A.
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p. 598 - 609
(2007/10/02)
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