- Novel positive allosteric modulators of A2B adenosine receptor acting as bone mineralisation promoters
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Small-molecules acting as positive allosteric modulators (PAMs) of the A2B adenosine receptor (A2B AR) could potentially represent a novel therapeutic strategy for pathological conditions characterised by altered bone homeostasis, including osteoporosis. We investigated a library of compounds (4-13) exhibiting different degrees of chemical similarity with three indole derivatives (1-3), which have been recently identified by us as PAMs of the A2B AR able to promote mesenchymal stem cell differentiation and bone formation. Evaluation of mineralisation activity of 4-13 in the presence and in the absence of the agonist BAY60-6583 allowed the identification of lead compounds with therapeutic potential as anti-osteoporosis agents. Further biological characterisation of one of the most performing compounds, the benzofurane derivative 9, confirmed that such a molecule behaves as PAM of the A2B AR.
- Barresi, Elisabetta,Giacomelli, Chiara,Marchetti, Laura,Baglini, Emma,Salerno, Silvia,Greco, Giovanni,Da Settimo, Federico,Martini, Claudia,Trincavelli, Maria Letizia,Taliani, Sabrina
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p. 286 - 294
(2020/12/22)
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- Fluorogenic Enzyme-Triggered Domino Reactions Producing Quinoxalin-2(1 H)-one-based Heterocycles
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A simple and effective biocompatible domino reaction triggered by a model protease and leading to the formation of strongly fluorescent quinoxalin-2(1H)-one N-heterocycles is described. Some positive attributes including versatility and the ability to pro
- Bonnin, Quentin,Chevalier, Arnaud,Dejouy, Garance,Michaudet, Cédric,Picquet, Michel,Renault, Kévin,Romieu, Anthony,Valverde, Ibai E.
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supporting information
p. 6494 - 6499
(2020/09/02)
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- Sequential Cu-Catalyzed Four- and Five-Component Syntheses of Luminescent 3-Triazolylquinoxalines
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3-Triazolylquinoxalines can be readily synthesized by applying two complementary synthetic protocols starting from heterocyclic π nucleophiles or (hetero)aryl glyoxylic acids in a consecutive four- or five-component reaction. Conceptually, the sequential use of a single cuprous salt for alkynylation and Cu-catalyzed alkyne-azide cycloaddition (CuAAC) in a one-pot fashion sets the stage for activation-alkynylation-cyclocondensation-CuAAC or glyoxylation-alkynylation-cyclocondensation-CuAAC sequences in good yields. The diversity-oriented generation of differently substituted 3-triazolylquinoxalines is an excellent entry to tunable emission solvatorchromic fluorophores with triazole ligation. The electronic structure, corroborated by DFT and TD-DFT calculations, rationalizes the charge transfer character of relevant absorptions and large Stokes shifts as well as the electronic innocence of the triazole substituents.
- Merkt, Franziska K.,Pieper, Konstantin,Klopotowski, Maximilian,Janiak, Christoph,Müller, Thomas J. J.
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supporting information
p. 9447 - 9455
(2019/04/17)
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- One-pot activation-alkynylation-cyclization synthesis of 1,5-diacyl-5-hydroxypyrazolines in a consecutive three-component fashion
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A consecutive three-component activation-alkynylation-cyclization reaction of (hetero)aryl glyoxylic acids, oxalyl chloride, arylacetylenes, and hydrazides efficiently forms 1,5-diacyl-5-hydroxypyrazolines in moderate to good yields. The structures were unambiguously corroborated by comprehensive NMR spectroscopy and X-ray structure analyses of selected derivatives.
- G?rgen, Christina,Boden, Katharina,Reiss, Guido J.,Frank, Walter,Müller, Thomas J.J.
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supporting information
p. 1360 - 1370
(2019/07/10)
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- Three-Component Activation/Alkynylation/Cyclocondensation (AACC) Synthesis of Enhanced Emission Solvatochromic 3-Ethynylquinoxalines
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2-Substituted 3-ethynylquinoxaline chromophores can be readily synthesized by a consecutive activation–alkynylation–cyclocondensation (AACC) one-pot sequence in a three-component manner. In comparison with the previously published four-component glyoxylation starting from electron-rich π-nucleophiles, the direct activation of (hetero)aryl glyoxylic acids allows the introduction of substituents that cannot be directly accessed by glyoxylation. By introducing N,N-dimethylaniline as a strong donor in the 2-position, the emission solvatochromicity of 3-ethynylquinoxalines can be considerably enhanced to cover the spectral range from blue–green to deep red–orange with a single chromophore in a relatively narrow polarity window. The diversity-oriented nature of the synthetic multicomponent reaction concept enables comprehensive investigations of structure–property relationships by Hammett correlations and Lippert–Mataga analysis, as well as the elucidation of the electronic structure of the emission solvatochromic π-conjugated donor–acceptor systems by DFT and time-dependent DFT calculations with the PBEh1PBE functional for a better reproduction of the dominant charge-transfer character of the longest wavelength absorption band.
- Merkt, Franziska K.,H?wedes, Simon P.,Gers-Panther, Charlotte F.,Gruber, Irina,Janiak, Christoph,Müller, Thomas J. J.
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supporting information
p. 8114 - 8125
(2018/04/02)
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- Novel synthesis of tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones via decarboxylative cyclization reaction of α-amino acids and α-ketoamides
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An efficient and practical method was developed for the synthesis of tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones based on the decarboxylative cyclization reaction of α-ketoamides and proline. In most cases, tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones were obtained with perfect diastereoselectivity to give trans-isomer in excellent yield.
- Wu, Jia-shou,Jiang, Hua-jiang,Yang, Jian-guo,Jin, Zheng-neng,Chen, Ding-ben
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supporting information
p. 546 - 551
(2017/01/16)
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- AMINOESTER DERIVATIVES
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The invention relates to novel compounds which are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Page/Page column 60
(2016/11/21)
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- Enantioselective Construction of 3-Hydroxypiperidine Scaffolds by Sequential Action of Light and Rhodium upon N-Allylglyoxylamides
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3-Hydroxypiperidine scaffolds were enantioselectively constructed in an atom-economical way by sequential action of light and rhodium upon N-allylglyoxylamides. In a formal sense, the allylic C-H bond was selectively cleaved and enantioselectively added a
- Ishida, Naoki,Ne?as, David,Masuda, Yusuke,Murakami, Masahiro
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supporting information
p. 7418 - 7421
(2015/06/30)
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- Organocatalytic Enantioselective Michael Reaction of Malononitrile with β,β-Disubstituted Nitroalkenes
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We have developed and optimized an enantioselective Michael reaction of malononitrile with β,β-disubstituted nitroalkenes. This reaction was catalyzed by a cinchona alkaloid derived thiourea catalyst, producing products of high yields (up to 98 %) and ste
- Chen, Shengwei,Lou, Qinxin,Ding, Yuyang,Zhang, Shasha,Hu, Wenhui,Zhao, Junling
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supporting information
p. 2437 - 2441
(2015/08/18)
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- Reductive cyclization of halo-ketones to form 3-hydroxy-2-oxindoles via palladium catalyzed hydrogenation: a hydrogen-mediated Grignard addition
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Abstract The reductive cyclization of N-oxoacyl ortho-bromoanilides to form 3-hydroxy-2-oxindoles under the conditions of palladium catalyzed hydrogenation is described. This work may be viewed as a prelude to intermolecular hydrogen-mediated Grignard-typ
- Shin, Inji,Ramgren, Stephen D.,Krische, Michael J.
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supporting information
p. 5776 - 5780
(2015/08/03)
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- Asymmetric friedel-crafts alkylation of α-substituted β-nitroacrylates: Access to β2,2-amino acids bearing indolic all-carbon quaternary stereocenters
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A highly enantioselective Friedel-Crafts alkylation reaction of indoles with acyclic α-substituted β-nitroacrylates is developed under the catalysis of Ni(ClO4)2-bisoxazoline complex at 1 mol % catalyst loading, affording chiral indolic β-nitroesters bearing all-carbon quaternary stereocenters in excellent yields and ees of up to 97%. Transformation of one of the products to β2,2-amino ester and tetrahydro-β-carboline through nitro reduction and sequential Pictet-Spengler cyclization was exemplified.
- Weng, Jian-Quan,Deng, Qiao-Man,Wu, Liang,Xu, Kai,Wu, Hao,Liu, Ren-Rong,Gao, Jian-Rong,Jia, Yi-Xia
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supporting information
p. 776 - 779
(2014/03/21)
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- Enantio- and chemoselective Br?nsted-acid/Mg(nBu) 2 catalysed reduction of α-keto esters with catecholborane
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The first enantio- and chemoselective Br?nsted-acid catalysed reduction of α-keto esters with catecholborane has been developed. The α-hydroxy esters were obtained under mild reaction conditions in virtually quantitative yields and excellent enantioselectivities. With slight modifications both enantiomers can be obtained without any loss of selectivity. This journal is the Partner Organisations 2014.
- Enders, Dieter,St?ckel, Bianca A.,Rembiak, Andreas
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supporting information
p. 4489 - 4491
(2014/04/17)
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- Solvatochromic fluorescent 2-substituted 3-ethynyl quinoxalines: Four-component synthesis, photophysical properties, and electronic structure
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2-Substituted 3-ethynylquinoxalines can be rapidly synthesized in generally excellent yields by a consecutive four-component synthesis starting from electron-rich π-nucleophiles, oxalyl chloride, terminal alkynes, and 1,2-diaminoarenes. The title compound
- Gers, Charlotte F.,Nordmann, Jan,Kumru, Ceyda,Frank, Walter,Müller, Thomas J. J.
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p. 3296 - 3310
(2014/05/06)
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- Modulation of A2B adenosine receptor by 1-Benzyl-3-ketoindole derivatives
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We have disclosed a series of 1-benzyl-3-ketoindole derivatives acting as either positive or negative modulators of the human A2B adenosine receptor (A2B AR) depending on small differences in their side chain. The new compounds were designed taking into account structural similarities between AR antagonists and ligands of the GABAA/benzodiazepine receptor. All compounds resulted totally inactive at A2A and A 3 ARs and showed small (8a,b) or none (7a,b, 8c and 9a,b) affinity for A1 AR. When tested on A2B AR-transfected CHO cells, 7a,b and 8a acted as positive modulators, whereas 8b,c and 9a,b acted as negative modulators, enhancing or weakening the NECA-induced increase of cAMP levels, respectively. Compounds 7-9 might be regarded as useful biological and pharmacological tools to explore the therapeutic potential of A2B AR modulators, while their 3-ketoindole scaffold might be taken as a reference to design new analogs.
- Taliani, Sabrina,Trincavelli, Maria Letizia,Cosimelli, Barbara,Laneri, Sonia,Severi, Elda,Barresi, Elisabetta,Pugliesi, Isabella,Daniele, Simona,Giacomelli, Chiara,Greco, Giovanni,Novellino, Ettore,Martini, Claudia,Da Settimo, Federico
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p. 331 - 337
(2013/10/21)
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- Nickel-catalyzed intramolecular nucleophilic addition of aryl or vinyl chlorides to α-ketoamides through C-Cl bond activation
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Nickeleophilic addition! The first example of a nickel-catalyzed direct intramolecular nucleophilic addition of aryl or vinyl chlorides to α-ketoamides through C-Cl bond activation is reported, which takes place under mild reaction conditions (see scheme).
- Hu, Jin-Xiu,Wu, Hao,Li, Chuan-Ying,Sheng, Wei-Jian,Jia, Yi-Xia,Gao, Jian-Rong
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supporting information; experimental part
p. 5234 - 5237
(2011/07/07)
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- Catalytic syntheses of N-heterocyclic ynones and ynediones by in situ activation of carboxylic acids with oxalyl chloride
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Breaking the bottleneck: α-Keto carboxylic acids and N-heterocyclic carboxylic acids are activated in situ with oxalyl chloride then catalytically alkynylated to give ynediones and N-heterocyclic ynones efficiently in a one-pot fashion. 5-Acylpyrazoles and 2-phenylaminopyrimidines, potentially interesting for pharmaceutical applications, are readily synthesized in concise one-pot, three-component syntheses. Copyright
- Boersch, Christina,Merkul, Eugen,Mueller, Thomas J. J.
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supporting information; experimental part
p. 10448 - 10452
(2011/12/05)
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- An investigation of structure-reactivity relationships of δ-alkenyl oximes; Competitive thermal reactions leading to cyclic nitrones and/or N-unsubstituted bicyclic isoxazolidines
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Thermal reactions of C-aryl δ-alkenyl oximes give N-unsubstituted bicylic lactone, lactam and pyrrolidine fused isoxazolidines by an intramolecular oxime olefin cycloaddition pathway (IOOC) and/or cyclic nitrones by an azaprotio cyclotransfer (APT) route; a number of factors, including the nature of the aryl group, the oxime geometry and the structure of the linker between the oxime and the terminal alkene, contribute to the competition. The nature of the aryl group, oxime geometry, and the structure of the linker between the oxime and the alkene influence the reactivity of C-aryl δ-alkenyl oximes.
- Doyle, Linda,Heaney, Frances
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experimental part
p. 7041 - 7049
(2010/10/18)
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- Asymmetrie aerobic oxidation of α-hydroxy acid derivatives by C 4-symmetric, vanadate-centered, tetrakisvanadyl(V) clusters derived from N-salicylidene-α-aminocarboxylates
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(Chemical Equation Presented) A series of chiral vanadyl(V) methoxides bearing 3-t-butyl-5-substituted N-salicylene-L-valinate and L-t-leucinate as chiral auxiliaries has been prepared. In all cases except the 3,5-di-t-butyl analogue, they exist as monomers both in solution and in the single crystal state. In the case of the 3,5-di-t-butyl analogue, the architectural nature of the vanadyl(V) complex highly depends on the base used during the complex formation event. A pentanuclear C4-symmetric complex was formed when potassium salts were employed instead of the corresponding sodium salts. A central vanadate(V) unit serves to grip four identical chiral monomelic vanadyl(V) units together, by which a potassium ion sits on top of the four flanking units through carbonyl coordinations and serves to hold the whole cluster by cooperation with the central vanadate(V) unit. In comparison with the corresponding monomelic vanadyl(V) methoxide complex, the cluster complex was utilized to facilitate the asymmetric aerobic oxidations of various racemic α-hydroxyesters, -amides, and -thioesters with excellent selectivity factors (krel 40 to >500).
- Chen, Chien-Tien,Bettigeri, Sampada,Weng, Shiue-Shien,Pawar, Vijay D.,Lin, Ya-Hui,Liu, Cheng-Yuan,Lee, Way-Zen
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p. 8175 - 8185
(2008/02/13)
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- ORGANIC COMPOUNDS
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Compounds of formula (I) in salt or zwitterionic form wherein, wherein R1, R2, R3, R4, R5, J, L and M have the meanings as indicated in the specification, are useful for treating conditions that are mediated by the muscarinic M3 receptor. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.
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Page 31; 32; 34
(2010/02/10)
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- Electro-organic synthesis 68.1 diastereoselective cathodic reduction of phenylglyoxylic acid attached to chiral auxiliaries
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Two chiral auxiliaries were attached to phenylglyoxylic acid as amides in 67-70% yield. Cyclic voltammetry of one amide in acetonitrile-pivalic acid (0.117 mol 1-1) shows that it is irreversibly reduced at -0.73 to -1.07 V (vs. Ag/AgCl) dependi
- Reufer, Christian,Zielinski, Claudia,Schaefer, Hans Juergen,Froehlich, Roland
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p. 1023 - 1037
(2007/10/03)
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- Isosteric replacement of the indole nucleus by benzothiophene and benzofuran in a series of indolylglyoxylylamine derivatives with partial agonist activity at the benzodiazepine receptor
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A number of benzothienyl- and benzofurylglyoxylylamine derivatives, which are analogues of previously described indolylglyoxylylamines with a partial agonist activity, are reported in this paper. They were synthesized and tested to verify the importance of the presence of the indole NH group in the interaction of this class of compounds with the benzodiazepine agonist receptor site, since it was reported in literature that a hydrogen bond donor group such as NH was not necessary to elicit an agonist response. Several thienylglyoxylylamine derivatives were also prepared and tested. None of the compounds showed a high affinity at the BzR, demonstrating that the indole NH plays a decisive role in the interaction of the agonist glyoxylylamine ligands with the receptor site.
- Da Settimo,Lucacchini,Marini,Martini,Primofiore,Senatore,Taliani
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p. 951 - 956
(2007/10/03)
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