- Exploring Stereochemical and Conformational Requirements at Cannabinoid Receptors for Synthetic Cannabinoids Related to SDB-006, 5F-SDB-006, CUMYL-PICA, and 5F-CUMYL-PICA
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Synthetic cannabinoid receptor agonists (SCRAs) represent the most rapidly expanding class of new psychoactive substances (NPSs). Despite the prevalence and potency of recent chiral indole-3-carboxamide SCRAs, few pharmacological data are available regarding the enantiomeric bias of these NPSs toward human CB1 and CB2 receptors. A series of homochiral indole-3-carboxamides derived from (S)- and (R)-α-methylbenzylamine and featuring variation of the 1-alkyl substituent were prepared, pharmacologically evaluated, and compared to related achiral congeners derived from cumyl- and benzylamine. Competitive binding assays demonstrated that all analogues derived from either enantiomer of α-methylbenzylamine (14-17) showed affinities for CB1 (Ki = 47.9-813 nM) and CB2 (Ki = 47.9-347 nM) that were intermediate to that of the corresponding benzylic (10-13, CB1 Ki = 550 nM to >10 μM; CB2 Ki = 61.7 nM to >10 μM) and cumyl derivatives (6-9, CB1 Ki = 12.6-21.4 nM; CB2 Ki = 2.95-24.5 nM). In a fluorometric membrane potential assay, all α-methylbenzyl analogues (excluding 17) were potent, efficacious agonists of CB1 (EC50 = 32-464 nM; Emax = 89-104%) and low efficacy agonists of CB2 (EC50 = 54-500 nM; Emax = 52-77%), with comparable or greater potency than the benzyl analogues and much lower potency than the cumyl derivatives, consistent with binding trends. The relatively greater affinity and potency of (S)-14-17 compared to (R)-14-17 analogues at CB1 highlighted an enantiomeric bias for this series of SCRAs. Molecular dynamics simulations provided a conformational basis for the observed differences in agonist potency at CB1 pending benzylic substitution.
- Ametovski, Adam,Macdonald, Christa,Manning, Jamie J.,Haneef, S. A. Syed,Santiago, Marina,Martin, Lewis,Sparkes, Eric,Reckers, Andrew,Gerona, Roy R.,Connor, Mark,Glass, Michelle,Banister, Samuel D.
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p. 3672 - 3682
(2020/11/18)
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- 3-(3,4,5-Trimethoxyphenylselenyl)-1 H -indoles and their selenoxides as combretastatin A-4 analogs: Microwave-assisted synthesis and biological evaluation
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A series of 3-(3,4,5-trimethoxyphenylselenyl)-1H-indoles and their selenoxides were designed as a new class of combretastatin A-4 (CA-4) analogs. The B ring and the cis double bond of CA-4 were replaced by an indole moiety and selenium atom, respectively. A facile and efficient microwave-assisted synthesis of 3-arylselenylindoles was developed to prepare the target compounds, which were then evaluated for antiproliferative activity against three human cancer cell lines using an MTT assay. Most of these compounds exhibited significant antiproliferative activity, with some showing nanomolar IC50 values. Tubulin polymerization and immunostaining experiments revealed that 13a potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a similar manner to CA-4. Docking studies demonstrated that 13a adopts an orientation similar to that of CA-4 at the colchicine binding site on tubulin.
- Wen, Zhiyong,Xu, Jingwen,Wang, Zhiwei,Qi, Huan,Xu, Qile,Bai, Zhaoshi,Zhang, Qian,Bao, Kai,Wu, Yingling,Zhang, Weige
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p. 184 - 194
(2015/01/08)
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- Selective N-alkylation of indoles with primary alcohols using a pt/HBEA catalyst?
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Pt-loaded HBEA (H+-exchanged BEA zeolite) is found to be an effective and reusable heterogeneous catalyst for regioselective N-alkylation of indoles with primary aliphatic and benzylic alcohols under additive-free conditions driven by the borrowing-hydrogen methodology. Structural and mechanistic studies suggest a cooperative mechanism of the Pt0 site on Pt metal clusters and the Br?nsted acid site of the zeolite, in which the Pt0 site is responsible for dehydrogenation/hydrogenation steps and the Br?nsted acid site is responsible for the regioselective condensation of indoles with aldehydes to the enamine intermediate.
- Hakim Siddiki,Kon, Kenichi,Shimizu, Ken-Ichi
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supporting information
p. 173 - 177
(2018/04/16)
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- FLUORINATION OF ARYL COMPOUNDS
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The invention provides compositions and methods of using the compositions in fluorinating aryl precursors containing a leaving group replaceable by fluoride ion. The compositions include a metal ion source, a fluoride ion source, and a compound, which is
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Paragraph 0087-0090
(2014/01/08)
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- Highly enantioselective hydrogenation of N-unprotected indoles using (S)-C10-BridgePHOS as the chiral ligand
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(S)-C10-BridgePHOS was successfully applied to a highly efficient Pd-catalyzed enantioselective hydrogenation of substituted indoles. The methodology was suitable for the hydrogenation of indoles substituted at the 2-, 3- and 2,3-positions. Products were obtained in quantitative conversion and up to 98% ee. The role the 2-position substituent plays in the hydrogenation process has been proposed. The methodology could be used as an alternative method to synthesize extremely important chiral indolines from N-unprotected indoles.
- Li, Chao,Chen, Jianzhong,Fu, Guanghong,Liu, Delong,Liu, Yangang,Zhang, Wanbin
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supporting information
p. 6839 - 6844
(2013/07/26)
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- Copper-mediated fluorination of aryl iodides
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The synthesis of aryl fluorides has been studied intensively because of the importance of aryl fluorides in pharmaceuticals, agrochemicals, and materials. The stability, reactivity, and biological properties of aryl fluorides can be distinct from those of the corresponding arenes. Methods for the synthesis of aryl fluorides, however, are limited. We report the conversion of a diverse set of aryl iodides to the corresponding aryl fluorides. This reaction occurs with a cationic copper reagent and silver fluoride. Preliminary results suggest this reaction is enabled by a facile reductive elimination from a cationic arylcopper(III) fluoride.
- Fier, Patrick S.,Hartwig, John F.
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supporting information; experimental part
p. 10795 - 10798
(2012/08/07)
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- Bronsted acid-catalyzed decarboxylative redox amination: Formation of N-alkylindoles from azomethine ylides by isomerization
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A Bronsted acid-catalyzed decarboxylative redox amination involving aldehydes with 2-carboxyindoline for the synthesis of N-alkylindoles is described. The decarboxylative condensations of aldehydes with 2-carboxyindoline produce azomethine ylides in situ,
- Mao, Hui,Wang, Sichang,Yu, Peng,Lv, Huiqing,Xu, Runsheng,Pan, Yuanjiang
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supporting information; experimental part
p. 1167 - 1169
(2011/04/16)
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- Tunable hydride transfer in the redox amination of indoline with aldehyde: An attractive intramolecular hydrogen-bond effect
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Hydride hijacked by "hydrogen"! N-Alkylindoles and N-alkylindolines were obtained in the redox amination of indoline with aldehyde, which was tuned by a hydrogen-bond effect. Salicylaldehyde gave the indoline-type product via intermolecular hydride transfer, while other aromatic aldehydes gave the indole-type product via intramolecular hydride transfer. Copyright
- Mao, Hui,Xu, Runsheng,Wan, Jieping,Jiang, Zhengyang,Sun, Cuirong,Pan, Yuanjiang
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supporting information; experimental part
p. 13352 - 13355
(2011/03/17)
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- Synthesis and structure-activity relationships of N-aryl(indol-3-yl)glyoxamides as antitumor agents
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The synthesis and study of the structure-activity relationships of cytotoxic compounds based on N-pyridinyl or N-aryl-2-(1-benzylindol-3-yl)glyoxamide skeleton, represented by the lead structures D-24241 and D-24851, are described. The presence of N-(pyridin-4-yl) moiety was crucial for activity and 2-[1-(4-chloro-3-nitrobenzyl)-1H-indol-3-yl]-2-oxo-N-(pyridin-4-yl)aceta mide (55), the most potent derivative, showed IC50 = 39 nM, 51 nM and 11 nM against HeLa/KB (human cervix carcinoma), L1210 (murine leukemia) and SKOV3 (human ovarian carcinoma) cell lines proliferation assay, respectively, as active as the lead compounds.
- Marchand, Pascal,Antoine, Maud,Baut, Guillaume Le,Czech, Michael,Baasner, Silke,Guenther, Eckhard
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experimental part
p. 6715 - 6727
(2009/12/06)
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- N-substituted indole-3-glyoxylamides having anti-asthmatic, antiallergic and immunosuppressant/immuno-modulating action
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The invention relates to novel N-substituted indole-3-glyoxylamides, to processes for their preparation and to their pharmaceutical use. The compounds have antiasthmatic, antiallergic and immunosuppressant/immunomodulating actions.
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Page column 6, 8
(2008/06/13)
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- Indolyl-3-glyoxylic acid derivatives having antitumor action
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The invention relates to the use of N-substituted indole-3-glyoxylamides of the general formula I as antitumor agents and to a pharmaceutical composition having antitumor action, characterized in that it contains at least one of the compounds of the gener
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- N-substituted indole-3 glyoxylamides having anti-asthmatic antiallergic and immunosuppressant/immuno-modulating action
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The invention relates to novel N-substituted indole-3-glyoxylamides, to processes for their preparation and to their pharmaceutical use. The compounds have antiasthmatic, antiallergic and immuno-suppressant/immunomodulating actions.
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