- A practical indium tribromide catalysed addition of indoles to nitroalkenes in aqueous media
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The 1,4-conjugate addition of indoles to nitroalkenes was efficiently carried out in aqueous media using a catalytic amount of indium tribromide (5 mol%). The reusability of the indium tribromide was tested by performing consecutive cycles with the same c
- Bandini, Marco,Melchiorre, Paolo,Melloni, Alfonso,Umani-Ronchi, Achille
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- Preparation of spiro[indole-3,5′-isoxazoles] via Grignard conjugate addition/spirocyclization sequence
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A highly efficient one-pot procedure combining conjugate addition of Grignard reagents to (2-nitroalkenyl)indoles and sub-sequent Br?nsted acid-assisted spirocyclization allowed for preparation of 4′H-spiro[indole-3,5′-isoxazoles] in a diastereomerically selective fashion. Utilization of alkyl Grignard reagents provided an easy access to 4′-alkylsubstituted derivatives hardly available by other means.
- Aksenov, Alexander V.,Aksenov, Dmitrii A.,Aksenov, Nicolai A.,Skomorokhov, Anton A.,Aleksandrova, Elena V.,Rubin, Michael
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- Nitrostyrenes as 1,4-CCNO-dipoles: diastereoselective formal [4+1] cycloaddition of indoles
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An unusual reactivity of nitrostyrenes in phosphorous acid was discovered, which permits the employment of these readily available synthons as 1,4-CCNO-dipole surrogates in a highly diastereoselective (4+1)-cycloaddition of indoles to afford 4′H-spiro[ind
- Aksenov, Alexander V.,Aksenov, Nicolai A.,Aksenov, Dmitrii A.,Khamraev, Vladislav F.,Rubin, Michael
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- Enantiospecific Allosteric Modulation of Cannabinoid 1 Receptor
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The cannabinoid 1 receptor (CB1R) is one of the most widely expressed metabotropic G protein-coupled receptors in brain, and its participation in various (patho)physiological processes has made CB1R activation a viable therapeutic modality. Adverse psychotropic effects limit the clinical utility of CB1R orthosteric agonists and have promoted the search for CB1R positive allosteric modulators (PAMs) with the promise of improved drug-like pharmacology and enhanced safety over typical CB1R agonists. In this study, we describe the synthesis and in vitro and ex vivo pharmacology of the novel allosteric CB1R modulator GAT211 (racemic) and its resolved enantiomers, GAT228 (R) and GAT229 (S). GAT211 engages CB1R allosteric site(s), enhances the binding of the orthosteric full agonist [3H]CP55,490, and reduces the binding of the orthosteric antagonist/inverse agonist [3H]SR141716A. GAT211 displayed both PAM and agonist activity in HEK293A and Neuro2a cells expressing human recombinant CB1R (hCB1R) and in mouse-brain membranes rich in native CB1R. GAT211 also exhibited a strong PAM effect in isolated vas deferens endogenously expressing CB1R. Each resolved and crystallized GAT211 enantiomer showed a markedly distinctive pharmacology as a CB1R allosteric modulator. In all biological systems examined, GAT211's allosteric agonist activity resided with the R-(+)-enantiomer (GAT228), whereas its PAM activity resided with the S-(-)-enantiomer (GAT229), which lacked intrinsic activity. These results constitute the first demonstration of enantiomer-selective CB1R positive allosteric modulation and set a precedent whereby enantiomeric resolution can decisively define the molecular pharmacology of a CB1R allosteric ligand.
- Laprairie, Robert B.,Kulkarni, Pushkar M.,Deschamps, Jeffrey R.,Kelly, Melanie E. M.,Janero, David R.,Cascio, Maria G.,Stevenson, Lesley A.,Pertwee, Roger G.,Kenakin, Terrence P.,Denovan-Wright, Eileen M.,Thakur, Ganesh A.
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- Direct conversion of 3-(2-nitroethyl)-1H-indoles into 2-(1H-indol-2-yl)acetonitriles
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The recently discovered [4+1]-spirocyclization of nitroalkenes to indoles provided a convenient new approach to 2-(1H-indol-2-yl)acetonitriles. However, this reaction was complicated by the formation of inert 3-(2-nitroethyl)-1H-indole byproducts. Herein,
- Aksenov, Alexander V.,Aksenov, Dmitrii A.,Aksenov, Nicolai A.,Aleksandrova, Elena V.,Grishin, Igor Yu.,Rubin, Michael,Sorokina, Elena A.,Wenger, Allison
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- Application of Fluorine- And Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators
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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.
- 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.
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p. 542 - 568
(2020/02/04)
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- Focused structure-activity relationship profiling around the 2-phenylindole scaffold of a cannabinoid type-1 receptor agonist-positive allosteric modulator: site-III aromatic-ring congeners with enhanced activity and solubility
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Specific tuning of cannabinoid 1 receptor (CB1R) activity by small-molecule allosteric modulators is a therapeutic modality with multiple properties inherently advantageous to therapeutic applications. We previously generated a library of unique CB1R posi
- Schaffer, Peter C.,Kulkarni, Pushkar M.,Janero, David R.,Thakur, Ganesh A.
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- Synthesis of Spiro[indole-3,5′-isoxazoles] with Anticancer Activity via a Formal [4 + 1]-Spirocyclization of Nitroalkenes to Indoles
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An acid-assisted [4 + 1]-cycloaddition of indoles with nitrostyrenes affords 4′H-spiro[indole-3,5′-isoxazoles] in a diastereomerically pure form. Several of these spirocyclic molecules exhibit promising anticancer activity by reducing viability and inducing differentiation of neuroblastoma cells.
- Aksenov, Alexander V.,Aksenov, Dmitrii A.,Arutiunov, Nikolai A.,Aksenov, Nicolai A.,Aleksandrova, Elena V.,Zhao, Zhenze,Du, Liqin,Kornienko, Alexander,Rubin, Michael
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p. 7123 - 7137
(2019/06/18)
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- Design of a Primary-Amide-Functionalized Highly Efficient and Recyclable Hydrogen-Bond-Donating Heterogeneous Catalyst for the Friedel-Crafts Alkylation of Indoles with β-Nitrostyrenes
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A primary-amide-functionalized metal organic framework, {[Zn2(2-BQBG)(BDC)2]·10H2O}n (1) (in which 2-BQBG = 2,2′-(butane-1,4-diylbis((quinolin-2-ylmethyl)azanediyl))diacetamide and BDC = 1,4-benzenedicarboxylate
- Markad, Datta,Mandal, Sanjay K.
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p. 3165 - 3173
(2019/03/26)
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- Bottom-Up Assembly of a Highly Efficient Metal-Organic Framework for Cooperative Catalysis
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In this study, we demonstrate a bottom-up assembly of a monomeric copper complex and a two-dimensional (2-D) heterometallic metal-organic framework (MOF) from a carboxylate-functionalized tridentate Schiff base ligand and metal ions. The obtained 2-D MOF
- Li, Changda,Tang, Haitong,Fang, Yu,Xiao, Zhifeng,Wang, Kunyu,Wu, Xiang,Niu, Helin,Zhu, Chengfeng,Zhou, Hong-Cai
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supporting information
p. 13912 - 13919
(2018/10/20)
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- Friedel-Crafts alkylation reaction with fluorinated alcohols as hydrogen-bond donors and solvents
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An effective and clean FC alkylation of indoles and electron-rich arenes with β-nitroalkenes in HFIP was reported. The desired products are formed rapidly in excellent yields under mild conditions without the need for any additional catalysts or reagents. Further, this methodology can be applied to one-pot synthesis of biologically active tryptamine derivatives.
- Tang, Ren-Jin,Milcent, Thierry,Crousse, Benoit
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p. 10314 - 10317
(2018/03/26)
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- Microwave-accelerated Conjugate Addition of 2-Arylindoles to Substituted β-Nitrostyrenes in the Presence of Ammonium Trifluoroacetate: An Efficient Approach for the Synthesis of a Novel Class of CB1 Cannabinoid Receptor Allosteric Modulators
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2-Arylindoles, in general, exhibit reduced reactivity towards the conjugate addition to substituted nitrostyrenes, when compared with indoles. We report here an efficient, expeditious, and high-yielding conjugate addition of 2-arylindoles to substituted β
- Kulkarni, Pushkar M.,Ranade, Ameya,Garai, Sumanta,Thakur, Ganesh A.
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p. 2079 - 2084
(2017/05/29)
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- Fiaud's Acid: A Br?nsted Acid Catalyst for Enantioselective Friedel-Crafts Alkylation of Indoles with 2-Alkene-1,4-diones
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Fiaud's acid (trans-1-hydroxy-2,5-diphenylphospholane 1-oxide), a phospholane-based phosphinic acid, is introduced as an efficient chiral Br?nsted acid catalyst that mediates the asymmetric Friedel-Crafts alkylation of indoles with 2-butene-1,4-diones. With a catalyst loading of 10 mol %, the reaction proceeded smoothly to afford 2-(indol-3-yl)butane-1,4-diones in high yield (up to 82%) and high enantioselectivity (up to 91% ee, one such product showed enhanced ee of 98% after recrystallization). The reaction conditions are sufficiently mild to tolerate sensitive functionality at room temperature and are therefore suitable for the synthesis of complex targets.
- Chatterjee, Sourav,Hintermann, Lukas,Mandal, Madhumita,Achari, Anushree,Gupta, Sreya,Jaisankar, Parasuraman
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supporting information
p. 3426 - 3429
(2017/07/15)
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- Allosteric modulators of CB1 cannabinoid receptors
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The present invention relates to novel heterocyclic derivatives which are allosteric modulators of cannabinoid receptor 1 (CB1) and which are useful for the treatment or prevention of neurological and psychiatric disorders associated with endocannabinoid
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Page/Page column 27; 28
(2017/02/24)
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- Catalyst-free dehydrative SN1-type reaction of indolyl alcohols with diverse nucleophiles "on water"
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A green and efficient dehydrative SN1-type reaction of indolyl alcohols with diverse nucleophiles was developed using water as the solvent, affording versatile 3-indolyl derivatives in high yields. The advantages of being catalyst-free, environmentally benign, and having a wide substrate scope and easy workup make it a promising method for preparation of indolyl compounds.
- Xiao, Jian,Wen, Hao,Wang, Liang,Xu, Lubin,Hao, Zhihui,Shao, Chang-Lun,Wang, Chang-Yun
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supporting information
p. 1032 - 1037
(2016/02/27)
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- Cerium(III)-catalyzed C3-acylation of indoles with nitroolefins
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A novel and efficient cerium(III)-catalyzed C3-selective acylation of N-H indoles using nitroolefins as acylating reagents was first developed. It was found that the use of CeCl3 as a catalyst achieves an unexpected and highly efficient C-C bon
- Feng, Cheng-Tao,Zhu, Hui-Zhi,Li, Zhong,Luo, Zaigang,Wu, Song-Song,Ma, Shi-Tang
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supporting information
p. 800 - 803
(2016/02/03)
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- Lewis Acid Activation of a Hydrogen Bond Donor Metal-Organic Framework for Catalysis
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A new metal-organic framework (MOF) composed of urea-containing tetracarboxylate struts was synthesized, and its hydrogen bonding capabilities were evaluated. The catalytic performance of this heterogeneous framework is enhanced through preactivation with silyl Lewis acids, leading to Friedel-Crafts reaction rates greater than those of common homogeneous hydrogen bond donors.
- Hall, Edward A.,Redfern, Louis R.,Wang, Michael H.,Scheidt, Karl A.
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p. 3248 - 3252
(2016/07/06)
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- Baker's yeast as an efficient biocatalyst for regioselective 1,4-conjugate addition of indoles to nitroolefins in aqueous medium
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The 1,4-conjugate addition of indoles to nitroolefins was efficiently carried out in aqueous media using baker's yeast as a biocatalyst at room temperature. The merits of the present method are operational simplicity, easy workup, utilization of an inexpensive catalyst, free from hazardous organic solvents and good yields of products. The generality of this method was demonstrated by synthesizing an array of diverse 3-substituted indole derivatives and could be extended for dialkylation of 1,4-bis-(2-nitrovinyl)benzene.
- Mane, Ananda,Lohar, Trushant,Salunkhe, Rajashri
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supporting information
p. 2341 - 2346
(2016/05/19)
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- Nitroalkenes as surrogates for cyanomethylium species in a one-pot synthesis of non-symmetric diarylacetonitriles
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Nitroalkenes were used as synthetic equivalents of the cyanomethylium cation in a modular, one-pot synthesis of 2-(3-indolyl)acetonitriles and 2,2-diarylacetonitriles involving electrophilic functionalization of aromatic and heteroaromatic C-H bond.
- Aksenov, Alexander V.,Aksenov, Nicolai A.,Dzhandigova, Zarema V.,Aksenov, Dmitrii A.,Rubin, Michael
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p. 106492 - 106497
(2016/01/15)
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- ALLOSTERIC MODULATORS OF CB1 CANNABINOID RECEPTORS
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The present invention relates to novel heterocyclic derivatives which are allosteric modulators of cannabinoid receptor 1 (CB1) and which are useful for the treatment or prevention of neurological and psychiatric disorders associated with endocannabinoid
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Paragraph 0083; 0084
(2013/07/19)
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- Catalyst free conjugate addition of indoles and pyrroles to nitro alkenes under solvent free condition (SFC): An effective greener route to access 3-(2-nitro-1-phenylethyl)-1H-indole and 2-(2-nitro-1-phenylethyl)-1H-pyrrole derivatives
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Catalyst free conjugate addition of reactive hetero aromatics (pyrrole and indoles) to nitro alkenes under solvent free condition is described. This method provides several advantages, such as operational simplicity, solvent-free conditions and good yield
- Habib, Pateliya Mujjamil,Kavala, Veerababurao,Kuo, Chun-Wei,Raihan, Mustafa J.,Yao, Ching-Fa
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experimental part
p. 7050 - 7056
(2010/09/15)
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- Efficient synthesis of 3-substituted indoles through a domino gold(I) chloride catalyzed cycloisomerization/C3-functionalization of 2-(alkynyl)anilines
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An efficient synthesis of 3-substituted indoles by a sequential approach involving gold(I) chloride catalyzed cycloisomerization/bis-addition and conjugate addition of 2-(alkynyl)anilines has been accomplished. A variety of 2-(alkynyl)anilines, aldehydes,
- Praveen,Karthikeyan,Perumal
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experimental part
p. 9244 - 9255
(2010/01/16)
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- An efficient method for the N-bromosuccinimide catalyzed synthesis of indolyl-nitroalkanes
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An efficient and practical method for the synthesis of indolyl-nitroalkane derivatives catalyzed by N-bromosuccinimide is described. The generality of this method was demonstrated by synthesizing an array of diverse 3-substituted indole derivatives by the reaction of different β-nitrostyrenes with various substituted indoles. Simple reaction conditions accompanied by good yields of indolyl-nitroalkanes are the merits of this methodology.
- Kuo, Chun-Wei,Wang, Chun-Chao,Fang, Hu-Lin,Raju, B. Rama,Kavala, Veerababurao,Habib, Pateliya Mujjamil,Yao, Ching-Fa
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experimental part
p. 3952 - 3963
(2009/12/26)
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- Mild and efficient Michael addition of activated olefins to indoles using TBAB as a catalyst: Synthesis of 3-substituted indoles
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A mild and efficient method for the synthesis of 3-substituted indoles by treatment of activated olefins with indoles using TBAB as a catalyst afforded the corresponding products in excellent yields. The method is general for the preparation of a wide var
- Suresh Babu,Rama Subba Rao,Sunitha,Sivaram Babu,Madhusudana Rao
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p. 1784 - 1791
(2008/09/20)
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- Friedel-Crafts alkylation of indoles with nitroolefins in the presence of β-cyclodextrin in water under neutral conditions
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Various indolyl nitroalkanes were prepared by the reaction of indoles with nitroolefins in the presence of β-cyclodextrin in water under neutral conditions. β-Cyclodextrin can be recovered and re-used several times without loss of activity.
- Kumar, Vydyula Pavan,Sridhar, Regati,Srinivas, Boga,Narender, Mendu,Rao, Kakulapati Rama
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p. 907 - 911
(2008/12/22)
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- Catalyst-free aqueous-mediated conjugative addition of indoles to β-nitrostyrenes
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A catalyst free aqueous-mediated alkylation of indoles with various β-nitrostyrenes was performed at elevated temperature. No catalyst, clean reaction conditions, simple workup procedure, easy isolation, viability for large scale preparation, and environm
- Habib, Pateliya Mujjamil,Kavala, Veerababurao,Kuo, Chun-Wei,Yao, Ching-Fa
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scheme or table
p. 7005 - 7007
(2009/04/10)
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- Glycerol as an efficient promoting medium for organic reactions
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Whereas the beneficial effect of water on reaction rate is decreased with an increase of the reactant's hydrophobicity, we report here that the use of glycerol as solvent was able to considerably accelerate the reaction rate of an organic reaction even st
- Gu, Yanlong,Barrault, Joel,Jerome, Francois
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supporting information; experimental part
p. 2007 - 2012
(2009/08/14)
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