15432-24-3Relevant articles and documents
Modular counter-Fischer?indole synthesis through radical-enolate coupling
Chung, Hyunho,Kim, Jeongyun,Gonzalez-Montiel, Gisela A.,Cheong, Paul Ha-Yeon,Lee, Hong Geun
supporting information, p. 1096 - 1102 (2021/01/26)
A single-electron transfer mediated modular indole formation reaction from a 2-iodoaniline derivative and a ketone has been developed. This transition-metal-free reaction shows a broad substrate scope and unconventional regioselectivity trends. Moreover, important functional groups for further transformation are tolerated under the reaction conditions. Density functional theory studies reveal that the reaction proceeds by metal coordination, which converts a disfavored 5-endo-trig cyclization to an accessible 7-endo-trig process.
Application of Fluorine- And Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators
Garai, Sumanta,Kulkarni, Pushkar M.,Schaffer, Peter C.,Leo, Luciana M.,Brandt, Asher L.,Zagzoog, Ayat,Black, Tallan,Lin, Xiaoyan,Hurst, Dow P.,Janero, David R.,Abood, Mary E.,Zimmowitch, Anaelle,Straiker, Alex,Pertwee, Roger G.,Kelly, Melanie,Szczesniak, Anna-Maria,Denovan-Wright, Eileen M.,Mackie, Ken,Hohmann, Andrea G.,Reggio, Patricia H.,Laprairie, Robert B.,Thakur, Ganesh A.
, p. 542 - 568 (2020/02/04)
Cannabinoid 1 receptor (CB1R) allosteric ligands hold a far-reaching therapeutic promise. We report the application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, β-arrestin 2), metabolic stability, and aqueous solubility. Two key analogs, GAT591 (6r) and GAT593 (6s), exhibited augmented allosteric-agonist and PAM activities in neuronal cultures, improved metabolic stability, and enhanced orthosteric agonist binding (CP55,940). Both analogs also exhibited good analgesic potency in the CFA inflammatory-pain model with longer duration of action over GAT211 while being devoid of adverse cannabimimetic effects. Another analog, GAT592 (9j), exhibited moderate ago-PAM potency and improved aqueous solubility with therapeutic reduction of intraocular pressure in murine glaucoma models. The SAR findings and the enhanced allosteric activity in this class of allosteric modulators were accounted for in our recently developed computational model for CB1R allosteric activation and positive allosteric modulation.
One-Pot Reaction between N-Tosylhydrazones and 2-Nitrobenzyl Bromide: Route to NH-Free C2-Arylindoles
Bzeih, Tourin,Zhang, Kena,Khalaf, Ali,Hachem, Ali,Alami, Mouad,Hamze, Abdallah
, p. 228 - 238 (2019/01/04)
A one-pot Barluenga coupling between N-tosylhydrazones and nitro-benzyl bromide, followed by deoxygenation of ortho-nitrostyrenes, and subsequent cyclization has been developed, providing a new way to synthesize various C2-arylindoles. This method exhibits a good substrate scope and functional group tolerance, and it allows an access to NH-free indoles, which can present a potential utility in medicinal chemistry applications.
Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1
Prior, Allan M.,Yu, Xufen,Park, Eun-Jung,Kondratyuk, Tamara P.,Lin, Yan,Pezzuto, John M.,Sun, Dianqing
, p. 5393 - 5399 (2017/11/20)
In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50 = 1.61 μM; 21, IC50 = 3.05 μM; and 27, IC50 = 3.34 μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR = 8.34, CD = 2.75 μM), while 7 showed the most potent CD value of 1.12 μM. A dual acting compound 24 showed aromatase inhibition (IC50 = 9.00 μM) as well as QR1 induction (CD = 5.76 μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3′-nitrogen coordinating with the heme group.
Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors
La Regina, Giuseppe,Bai, Ruoli,Rensen, Whilelmina Maria,Di Cesare, Erica,Coluccia, Antonio,Piscitelli, Francesco,Famiglini, Valeria,Reggio, Alessia,Nalli, Marianna,Pelliccia, Sveva,Da Pozzo, Eleonora,Costa, Barbara,Granata, Ilaria,Porta, Amalia,Maresca, Bruno,Soriani, Alessandra,Iannitto, Maria Luisa,Santoni, Angela,Li, Junjie,Miranda Cona, Marlein,Chen, Feng,Ni, Yicheng,Brancale, Andrea,Dondio, Giulio,Vultaggio, Stefania,Varasi, Mario,Mercurio, Ciro,Martini, Claudia,Hamel, Ernest,Lavia, Patrizia,Novellino, Ettore,Silvestri, Romano
, p. 123 - 149 (2013/03/13)
New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.
Synthesis of 2-arylindole derivatives and evaluation as nitric oxide synthase and NFκB inhibitors
Yu, Xufen,Park, Eun-Jung,Kondratyuk, Tamara P.,Pezzuto, John M.,Sun, Dianqing
, p. 8835 - 8847 (2013/01/15)
Development of small molecule drug-like inhibitors blocking both nitric oxide synthase and NFκB could offer a synergistic therapeutic approach in the prevention and treatment of inflammation and cancer. During the course of evaluating the biological potential of a commercial compound library, 2-phenylindole (1) displayed inhibitory activity against nitrite production and NFκB with IC50 values of 38.1 ± 1.8 and 25.4 ± 2.1 μM, respectively. Based on this lead, synthesis and systematic optimization have been undertaken in an effort to find novel and more potent nitric oxide synthase and NFκB inhibitors with antiinflammatory and cancer preventive potential. First, chemical derivatizations of 1 and 2-phenylindole-3-carboxaldehyde (4) were performed to generate a panel of N-alkylated indoles and 3-oxime derivatives 2-7. Second, a series of diversified 2-arylindole derivatives (10) were synthesized from an array of substituted 2-iodoanilines (8) and terminal alkynes (9) by applying a one-pot palladium catalyzed Sonogashira-type alkynylation and base-assisted cycloaddition. Subsequent biological evaluations revealed 3-carboxaldehyde oxime and cyano substituted 2-phenylindoles 5 and 7 exhibited the strongest nitrite inhibitory activities (IC50 = 4.4 ± 0.5 and 4.8 ± 0.4 μM, respectively); as well as NFκB inhibition (IC50 = 6.9 ± 0.8 and 8.5 ± 2.0 μM, respectively). In addition, the 6′-MeO-naphthalen-2′-yl indole derivative 10at displayed excellent inhibitory activity against NFκB with an IC50 value of 0.6 ± 0.2 μM.
Palladium-catalyzed synthesis of indoles via ammonia cross-coupling-alkyne cyclization
Alsabeh, Pamela G.,Lundgren, Rylan J.,Longobardi, Lauren E.,Stradiotto, Mark
supporting information; experimental part, p. 6936 - 6938 (2011/08/06)
The synthesis of indoles via the metal-catalyzed cross-coupling of ammonia is reported for the first time; the developed protocol also allows for the unprecedented use of methylamine or hydrazine as coupling partners. These Pd/Josiphos-catalyzed reactions proceed under relatively mild conditions for a range of 2-alkynylbromoarenes.
RENIN INHIBITORS
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Page/Page column 125, (2010/11/17)
The invention relates to compounds having the formula: STR wherein the variables are as defined herein. The invention further relates to methods of making and using these compounds, intermediates which can be used to make the compounds, and pharmaceutical compositions, kits and articles of manufacture which contain the compounds.
Scope of the suzuki-Miyaura cross-coupling reactions of potassium heteroaryltrifluoroborates
Molander, Gary A.,Canturk, Belgin,Kennedy, Lauren E.
supporting information; experimental part, p. 973 - 980 (2009/07/11)
A wide variety of bench-stable potassium heteroaryltrifluoroborates were prepared, and general reaction conditions were developed for their cross-coupling to aryl and heteroaryl halides. The cross-coupled products were obtained in good to excellent yields. This method represents an efficient and facile installation of heterocyclic building blocks onto preexisting organic substructures.
One-pot/four-step/palladium-catalyzed synthesis of indole derivatives: The combination of heterogeneous and homogeneous systems
Sakai, Hayato,Tsutsumi, Ken,Morimoto, Tsumoru,Kakiuchia, Kiyomi
supporting information; experimental part, p. 2498 - 2502 (2009/08/14)
One-pot, four-step syntheses of indoles using both solid-supported heterogeneous and homogeneous palladium catalysts and reagents were carried out. Such a combination of these two-phase catalysts and reagents causes a dramatic increase in yield, and it is a simple process. The presented methodology is effective for four-step reactions to provide various functionalized indoles.
