- Synthesis of CF3-Containing Spirocyclic Indolines via a Red-Light-Mediated Trifluoromethylation/Dearomatization Cascade
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A red-light-mediated nPr-DMQA+-catalyzed cascade intramolecular trifluoromethylation and dearomatization of indole derivatives with Umemoto's reagent has been developed. This protocol provides a facile and efficient approach for the construction of functionalized and potentially biologically important CF3-containing 3,3-spirocyclic indolines with moderate to high yields and excellent diastereoselectivities under mild conditions. The success of multiple gram-scale (1 and 10 g) experiments further highlights the robustness and practicality of this protocol and the merit of the employment of red light. Mechanistic studies support the formation of a crucial CF3 radical species and a dearomatized benzyl carbocation intermediate.
- Gianetti, Thomas L.,Mei, Liangyong,Moutet, Jules,Stull, Savannah M.
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p. 10640 - 10653
(2021/07/31)
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- Unified Synthesis of Polycyclic Alkaloids by Complementary Carbonyl Activation**
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A complementary dual carbonyl activation strategy for the synthesis of polycyclic alkaloids has been developed. Successful applications include the synthesis of tetracyclic alkaloids harmalanine and harmalacinine, pentacyclic indoloquinolizidine alkaloid nortetoyobyrine, and octacyclic β-carboline alkaloid peganumine A. The latter synthesis features a protecting-group-free assembly and an asymmetric disulfonimide-catalyzed cyclization. Furthermore, formal syntheses of hirsutine, deplancheine, 10-desbromoarborescidine A, and oxindole alkaloids rhynchophylline and isorhynchophylline have been achieved. Finally, a concise synthesis of berberine alkaloid ilicifoline B was completed.
- Christmann, Mathias,He, Guoli,List, Benjamin
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supporting information
p. 13591 - 13596
(2021/05/07)
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- 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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p. 8049 - 8054
(2020/11/02)
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- Hypervalent Iodine-Mediated Cyclization of Homotryptamine Derivatives
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A facile and efficient cyclization of homotryptamines and their derivatives has been established for the construction of 4a-chlorotetrahydropyrido[2,3-b]indoles and 3,3-spirocyclic 3H-indoles using hypervalent iodine (1-chloro-1,2-benziodoxol-3-one) under mild conditions. The broad substrate scope and successful gram-scale experiment grant this metal-free transformation great potential for further application.
- Jiang, Xinpeng,Zhu, Weijie,Yang, Liechao,Zheng, Zicong,Yu, Chuanming
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supporting information
p. 2268 - 2274
(2019/04/03)
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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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p. 4004 - 4019
(2018/05/07)
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- Synthesis and Biological Evaluation of an Indazole-Based Selective Protein Arginine Deiminase 4 (PAD4) Inhibitor
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Protein arginine deiminase 4 (PAD4) is a calcium-dependent enzyme that catalyzes the conversion of arginine to citrulline within target proteins. Dysregulation of PAD4 has been implicated in a number of human diseases, including rheumatoid arthritis and other inflammatory diseases as well as cancer. In this study, we report on the design, synthesis, and evaluation of a new class of haloacetamidine-based compounds as potential PAD4 inhibitors. Specifically, we describe the identification of 4,5,6-trichloroindazole 24 as a highly potent PAD4 inhibitor that displays >10-fold selectivity for PAD4 over PAD3 and >50-fold over PAD1 and PAD2. The efficacy of this compound in cells was determined by measuring the inhibition of PAD4-mediated H4 citrullination in HL-60 granulocytes.
- Tjin, Caroline Chandra,Wissner, Rebecca F.,Jamali, Haya,Schepartz, Alanna,Ellman, Jonathan A.
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supporting information
p. 1013 - 1018
(2018/10/02)
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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 34; 35; 45; 60; 61
(2017/09/24)
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- Potentiation of Francisella resistance to conventional antibiotics through small molecule adjuvants
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A screen of 20 compounds identified small molecule adjuvants capable of potentiating antibiotic activity against Francisella philomiragia. Analogue synthesis of an initial hit compound led to the discovery of a potentially new class of small molecule adjuvants containing an indole core. The lead compound was able to lower the MIC of colistin by 32-fold against intrinsically resistant F. philomiragia.
- Stephens, Matthew D.,Hubble, Veroncia B.,Ernst, Robert K.,Van Hoek, Monique L.,Melander, Roberta J.,Cavanagh, John,Melander, Christian
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supporting information
p. 128 - 131
(2016/01/30)
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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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- Access to Spirocyclized Oxindoles and Indolenines via Palladium-Catalyzed Cascade Reactions of Propargyl Carbonates with 2-Oxotryptamines and Tryptamines
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(Chemical Equation Presented). Reported here are methods for the direct construction of a range of spirocyclized oxindoles and indolenines in good to excellent yields. Specifically, we report the palladium-catalyzed reactions of oxindoles and indoles, both functioning as bis-nucleophiles, with propargyl carbonates to afford spirocyclic products having an exocyclic double bond on the newly formed ring. The reaction proceeds through a process wherein the first nucleophilic unit on the oxindole or indole reacts with an allenyl-palladium species, formed from oxidative addition of Pd(0) to propargyl carbonates, to generate a π-allyl palladium intermediate that then reacts further with the second nucleophilic component of the oxindole or indole. The cascade process forges two bonds en route to spirocyclized oxindole and indolenine products. The use of chiral phosphines renders the cyclization sequence enantioselective, providing spirocyclic products with modest to good enantioselectivities.
- Nibbs, Antoinette E.,Montgomery, Thomas D.,Zhu, Ye,Rawal, Viresh H.
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p. 4928 - 4941
(2015/06/02)
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- Asymmetric dearomatization of indoles through a Michael/Friedel-Crafts-Type cascade to construct polycyclic spiroindolines
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A highly efficient asymmetric dearomatization of indoles was realized through a cascade reaction between 2-isocyanoethylindole and alkylidene malonates catalyzed by a chiral N,N-dioxide/MgII catalyst. Fused polycyclic indolines containing three stereocenters were afforded in good yields with excellent diastereo- and enantioselectivities through a Michael/Friedel-Crafts/Mannich cascade. When 2-substituted 2-isocyanoethylindoles were used, spiroindoline derivatives were obtained through a Michael/Friedel-Crafts reaction.
- Zhao, Xiaohu,Liu, Xiaohua,Mei, Hongjiang,Guo, Jing,Lin, Lili,Feng, Xiaoming
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p. 4032 - 4035
(2015/03/30)
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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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- Metabolism and metabolites of dithiocarbamates in the plant pathogenic fungus leptosphaeria maculans
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Synthetic compounds containing a dithiocarbamate group are known to have a variety of biological effects and applications including antifungal, herbicidal, and insecticidal application. Leptosphaeria maculans is a fungal pathogen of crucifers able to detoxify efficiently the only plant natural product containing a dithiocarbamate group, the phytoalexin brassinin. To evaluate the effects of dithiocarbamates on L. maculans, a number of structurally diverse S-methyl dithiocarbamates containing indolyl, biphenyl, and benzimidazolyl moieties were synthesized, and their antifungal activities and metabolism by L. maculans were investigated. All dithiocarbamates were transformed by L. maculans through hydrolysis to the corresponding amines, which were less antifungal than the parent compounds. Two dithiocarbonates were shown to be much less antifungal than the corresponding dithiocarbamates. Results of this investigation indicate that S-methyl dithiocarbamates are not useful inhibitors of L. maculans and that their rates of transformation by L. maculans did not correlate with the antifungal activity of the particular compound.
- Pedras, M. Soledade C.,Sarma-Mamillapalle, Vijay K.
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p. 7792 - 7798
(2012/10/08)
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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 16
(2009/12/02)
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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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- 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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- Syntheses of 5a′-homo-vinblastine and congeners designed to establish structural determinants for isolation of atropisomers
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The syntheses of 5a′-homo-vinblastine (3a) and its C-20′ methyl congener 62a were achieved. In contrast to vinblastine, these compounds did not allow isolation of atropisomers because of their lower conformational inversion barrier. However, annelation of a six-membered ring to the conformationally mobile D′-piperidine ring provided an isolated atropisomer 81a, which could be converted to its lower energy conformation 65a on heating. The 5a′-homo-vinblastine congeners 3a, 62a, and 65a showed vinblastine-like inhibition of tubulin polymerization and cytotoxicity to L1210 leukemia cells, albeit at lower potency for the latter activity, than that found with the corresponding compounds in the vinblastine series.
- Kuehne,Cowen,Xu,Borman
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p. 5303 - 5316
(2007/10/03)
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- Highly potent inhibitors of the Grb2-SH2 domain
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Highly potent inhibitors of the Grb2-SH2 domain have been synthesized. They share the common sequence: Ac-Pmp-Ac6c-Asn-NH-(3-indolyl-propyl). Different substituents at the 3-indolyl-propylamine C-terminal group were explored to further improve the activity. This is the first example of inhibitors of SH2 domains with sub-nanomolar affinity reported to date.
- Schoepfer, Joseph,Fretz, Heinz,Gay, Brigitte,Furet, Pascal,Garcia-Echeverria, Carlos,End, Nicole,Caravatti, Giorgio
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p. 221 - 226
(2007/10/03)
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