- Metal-free N-arylation of indolines with diaryliodonium salts
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The N-arylation of indolines using diaryliodonium salts as electrophilic arylating reagents is described. Without the use of any additional additives, the desired N-aryl indolines could be obtained in up to 85% yield.
- Riedmüller, Stefan,Nachtsheim, Boris J.
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- Copper(II)-Catalyzed Direct C-H (Hetero)arylation at the C3 Position of Indoles Assisted by a Removable N, N-Bidentate Auxiliary Moiety
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The regioselective arylation of inert C3-H bonds in indoles reacting with arylboronates via effective copper-mediated catalysis with the aid of a facile and removable 2-pyridinylisopropyl (PIP) group without ligand participation is reported. This newly established method features high compatibility with diverse functional groups between coupling partners, including both indole substrates and arylboron reagents, consequentially leading to operational simplicity and providing access to generate the desired arylated products in good to excellent yields of up to 97%. Synthetically, the PIP-derived amide moiety could subsequently be readily removed under mild reaction conditions to produce useful indole carboxylic acids for further transformation.
- Xu, Hai-Feng,Pan, You-Lu,Li, Gang-Jian,Hu, Xu-Yang,Chen, Jian-Zhong
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- Synthesis, spectroscopic identification and molecular docking of certain N-(2-[2-(1H-Indol-2-ylcarbonyl) hydrazinyl](oxo)acetyl phenyl)acetamides and N-[2-(2-[2-(Acetylamino)phenyl](oxo)acetyl hydrazinyl)-2-oxoethyl]-1H-indole-2-carboxamides: New antimicrobial agents
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N-(2-[2-(1H-Indol-2-ylcarbonyl)hydrazinyl](oxo)acetyl phenyl)acetamides (5a–h) and N-[2-(2-[2-(acetylamino)phenyl](oxo)acetyl hydrazinyl)-2-oxoethyl]-1H-indole-2-carboxamides (5i–l) were synthesized and characterized with different analytical tools. N-Acetylisatines 4a–d were subjected to ring opening at their C2 carbons with the aid of different indole-bearing hydrazides 3a,b and 7 to afford the respective glyoxylamides 5a–l. The antimicrobial activity of the target compounds 5a–l was assessed with the aid of Diameter of the Inhibition Zone (DIZ) and Minimum Inhibitory Concentration (MIC) assays against a panel of Gram-positive and Gram-negative bacteria and certain fungal strains. The antimicrobial screening revealed that Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans are the most sensitive microorganisms towards the synthesized compounds 5a–l. In addition, compounds 5c and 5h emerged as the most active congeners towards Staphylococcus aureus and Candida albicans, respectively. Molecular docking studies revealed the possible binding mode of compounds 5c and 5h to their target proteins.
- Almutairi, Maha S.,Zakaria, Azza S.,Al-Wabli, Reem I.,Hubert Joe,Abdelhameed, Ali S.,Attia, Mohamed I.
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- 1H-Azirines as Intermediates in the Photolysis of 1,2,3-Triazoles
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Photolytic conversion of 1-aryl-1,2,3-triazoles (5) and (14) into the 'rearranged' indoles (4) and (15), respectively, provides the first evidence for antiaromatic 1H-azirines, e.g. (8), as reactive intermediates in a photochemical reaction.
- Mitchell, Glynn,Rees, Charles W.
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- A General Non-Reductive Method for the Desulfenylation of 3-Indolyl Sulfides
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In trifluoroacetic acid, in the presence of thiosalicyclic acid as a trapping agent, 3-indolyl sulfides bearing a wide variety of substituents are smoothly and rapidly desulfenylated to the corresponding 3-unsubstituted indoles.
- Hamel, Pierre,Zajac, Nicolas,Atkinson, Joseph G.,Girard, Yves
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- RCM in indoles. A new entry to the mitosene skeleton
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The RCM metathesis reaction catalyzed by Grubbs' ruthenium catalyst is used with a series of 1,2-disubstituted indoles leading with excellent yields to tricyclic compounds. When applied to 1-allyl-2-vinylindoles this methodology allows a new entry to the mitosene skeleton.
- González-Pérez, Patxi,Pérez-Serrano, Leticia,Casarrubios, Luis,Domínguez, Gema,Pérez-Castells, Javier
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- Synthesis of isobrassilexin, a biologically active isomer of brassilexin, a cruciferae phytoalexin
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The synthesis of isobrassilexin 2, a hitherto non natural indoloisothiazole is reported (two steps, 43% yield). This substance, an isomer of brassilexin 1 has shown important biological properties in vitro.
- Barbier,Devys,Tempete,Kollmann,Bousquet
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- Trapping of the putative cationic intermediate in the Morin rearrangement with carbon nucleophiles
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This paper presents reactions in which the putative cationic intermediate in the Morin rearrangement is trapped by aromatic carbon nucleophiles (indoles and furans). For example, reaction of sulfoxide 27 with trifluoroacetic acid in chloroform provides, among other products, indole 29 and indoline 30. The indoline was shown to be in equilibrium with the nine-membered ring bridged indole 31. Other examples of Morin rearrangement-trapping reactions are presented, and mechanisms for these transformations are proposed.
- Freed,Hart,Magomedov
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- Rapid and easy access to indoles via microwave-assisted Hemetsberger-Knittel synthesis
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Hemetsberger-Knittel indole synthesis can be carried out under microwave activation. The optimum reaction conditions were found by using different solvents and by varying irradiation times and temperature. After 10 min of microwave irradiation, high conversion into the corresponding indole products was achieved without formation of any side products.
- Lehmann, Frank,Holm, Melanie,Laufer, Stefan
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- Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis
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Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD+)-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD+
- Arnhof, Heribert,Bader, Gerd,Bruchhaus, Jens,Burkard, Michelle,Ciftci, Tuncay,Dahmann, Georg,Du, Alicia,Ettmayer, Peter,Fett, Thomas N.,Garavel, Géraldine,Gerstberger, Thomas,Haering, Daniela,Harrer, Christoph,Hofbauer, Karin S.,Kessler, Dirk,Kousek, Roland,Li, Dongyang,Li, Yali,Lv, Xiaobing,Martinelli, Paola,Mayer, Moriz,McConnell, Darryl B.,Mischerikow, Nikolai,Mitzner, Sophie,Pearson, Mark,Peric-Simov, Biljana,Quant, Jens,Rinnenthal, Joerg,Rumpel, Klaus,Savarese, Fabio,Scherbantin, Yvonne,Schnitzer, Renate,Scholz, Guido,Schrenk, Andreas,Sharps, Bernadette,Sommergruber, Wolfgang,Treu, Matthias,Weinstabl, Harald,Wolkerstorfer, Bernhard,Zahn, Stephan K.,Zhang, Xuechun,Zoephel, Andreas
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- Synthesis of enynoindoles via vinyl and ethynyl indoles
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A convenient synthesis of indoles bearing allyl, ethynyl, and/or propargyl moieties is described starting from indole or indole-2-carboxylic acid.
- Pérez-Serrano, Leticia,Casarrubios, Luis,Domínguez, Gema,González-Pérez, Patxi,Pérez-Castells, Javier
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- Study of molecular structure, chemical reactivity and first hyperpolarizability of a newly synthesized N-(4-oxo-2-phenylquinazolin-3(4H)-yl)-1H-indole-2-carboxamide using spectral?analysis
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A series of novel Quinazolinone derivatives were synthesized and characterized by various spectroscopic techniques. The nature of reactants and products of chemical reactions has been determined using thermodynamic parameters (H, G, S). The TD–DFT calculation of the compound shows that electronic excitations is n→π? in nature and compounds having intramolecular hydrogen bonding is obvious in 1H NMR, 13C NMR, FT–IR measurements and ESP map. In 1H NMR signal of the indolic NH protons appears at 7.26 ppm shows that intramolecular hydrogen is present in compounds. The vibrational analysis designates the presence of intramolecular hydrogen bonding N12–H34?O21 shows in lowering of NH and CO stretching vibrations frequency. The local reactivity descriptors Fukui functions (fk+, fk–), local softness's (sk+, sk–) and electrophilicity indices (ωk+, ωk–) determine the reactive sites within molecule. The computed first hyperpolarizability (β0) found to be 10.2254×10?30esu indicating that the compound is non–linear optical (NLO) material.
- Chaudhary, Aniruddh Prasad,Bharti, Shailendra Kumar,Kumar, Santosh,Ved, Kumar,Padam, Kant
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- Base-assisted intramolecular c-n coupling reaction from nh2-bound cyclopalladated l -phenylalanine to indoline-2-carboxylic acid
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The deprotonative intramolecular-amination reaction of phenylalanine-derived palladacycles has been investigated to highlight a facile carbonate-assisted N-H activation before the C-N bond formation. A major counterion effect led to divergent pathways whereby the SPhos-Pd complexes with iodine, triflate, or trifluoroacetate anions were key intermediates to afford access to (S)-2-indolinecarboxylic acid derivatives.
- Afonso, Carlos,Brière, Jean-Fran?ois,Coufourier, Sébastien,Gandon, Vincent,Hoarau, Christophe,Jacquin-Labarre, Aurélien,Journot, Guillaume,Le Foll, Alexandra,Levacher, Vincent,Tamion, Rodolphe
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- Efficient synthesis of the first n-methyloxoarcyriaflavin including an original central seven-membered cycle
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A new route to the first N-methyloxoarcyriaflavin was designed. The compound was obtained by a palladium-catalyzed Stille cross-coupling reaction, followed by an electrophilic cyclization onto a C-2 indolic position as a key step. Georg Thieme Verlag Stuttgart · New York.
- Bourderioux, Aurelie,Ouach, Aziz,Beneteau, Valerie,Merour, Jean-Yves,Routier, Sylvain
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- A Novel Sc(OTf)3-Catalyzed (2+2+1)-Cycloannulation/Aza-Friedel–Crafts Alkylation Sequence toward Multicyclic 2-Pyrrolines
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The rapid assembly of molecular complexity continues to be at the forefront of novel reaction development. In the pursuit of that goal, we herein report a novel Sc(OTf)3-catalyzed, one-pot multicomponent reaction that furnishes complex multicyclic 2-pyrrolines with excellent overall yields and perfect diastereocontrol. This process is based on our previously established (2+2+1)-cycloannulation of in situ generated 1-azaallyl cations, 1,3-dicarbonyls and primary amines. The newly formed and highly reactive aminal moiety is readily substituted with indoles and pyrroles both as external and internal π-nucleophiles to provide densely functionalized N-heterocycles with four new σ-bonds and two vicinal quaternary stereogenic centers. In addition, DFT calculations have been conducted to further characterize the intermediate 1-azaallyl cations.
- Schlegel, Marcel,Coburger, Peter,Schneider, Christoph
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- Indolylbenzimidazole-based ligands catalyze the coupling of arylboronic acids with aryl halides
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A novel class of compounds bearing indole and benzimidazole rings was designed and easily synthesized from 2-indolecarboxylic acid and o-phenylenediamine. The catalytic system derived from a 2-indolylbenzimidazole-based ligand and Pd(OAc)2 in situ could lead to complete conversion of aryl bromides at 0.5?mol% Pd loading under mild reaction conditions. In the presence of a catalyst, sterically hindered biaryls were selectively generated in excellent yields by adjusting reaction parameters through the coupling of arylboronic acids with aryl halides. The efficiency of this reaction was demonstrated by its compatibility with various functional groups.
- Wang, Meng-Pei,Chiu, Chien-Cheng,Lu, Ta-Jung,Lee, Dong-Sheng
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- Enantioselective arylative dearomatization of indoles via pd-catalyzed intramolecular reductive heck reactions
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A highly enantioselective intramolecular arylative dearomatization of indoles via palladium-catalyzed reductive Heck reactions was developed. The new strategy led to a series of optically active indolines bearing C2-quaternary stereocenters in modest to good yields with excellent enantioselectivities (up to 99% ee).
- Shen, Chong,Liu, Ren-Rong,Fan, Ren-Jie,Li, Ying-Long,Xu, Teng-Fei,Gao, Jian-Rong,Jia, Yi-Xia
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- Direct Observation of 1-Azafulven-6-one and Annelated Derivatives
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1-Azafulven-6-one, 2-carbonyl-2H-indole, 5-carbonyl-5H-furopyrrole, and thieno- and pyrrolo-analogues are isolated at low temperatures following thermal elimination of water or methanol from the corresponding carboxylic acids or esters; the azafulvenones dimerise at -100 to -40 deg C to diketopiperazine derivatives.
- Gross, Gerhard,Wentrup, Curt
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- Synthesis of new functionalized indoles based on ethyl indol-2-carboxylate
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Successful alkylations of the nitrogen of ethyl indol-2-carboxylate were carried out using aq. KOH in acetone. The respective N-alkylated acids could be obtained without separating the N-alkylated esters by increasing the amount of KOH and water. The use of NaOMe in methanol led to transesterification instead of the alkylation, while the use of NaOEt led to low yields of the N-alkylated acids. Hydrazinolysis of the ester gave indol-2-carbohydrazide which then was allowed to react with different aromatic aldehydes and ketones in ethanol catalyzed by acetic acid. Indol-2-thiosemicarbazide was used in a heterocyclization reaction to form thiazoles. The new structures were confirmed using NMR, mass spectrometry and X-ray single crystal analysis.
- Boraei, Ahmed T. A.,El Ashry, El Sayed H.,Barakat, Assem,Ghabbour, Hazem A.
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- Indole- and indoline-based kainate analogues with antagonist activity at ionotropic glutamate receptors
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A conformationally constrained, indole-based kainate analogue was designed based on Gouaux's X-ray structure of kainic acid bound to an iGluR2(S1S2) construct, a structural model for AMPA/kainate ionotropic glutamate receptors. In contrast to the parent kainic acid, a potent agonist, this compound, along with three structurally related analogues derived from synthetic intermediates, exhibited antagonist behavior towards KAR expressed in oocytes, a result that is rationalized by molecular modeling studies.
- Shou, Xiaohong,Miledi, Ricardo,Chamberlin, A. Richard
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- Binding trimethyllysine and other cationic guests in water with a series of indole-derived hosts: Large differences in affinity from subtle changes in structure
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The binding of a series of indole-derived hosts to various ammonium cations in pure, buffered water is investigated using both solution phase 1H NMR studies and computational modeling. These hosts can engage their targets via the cation-pi interaction, electrostatic attraction, and the hydrophobic effect. The hydrophobic effect is shown to be a dominant influence in the strength of the binding interactions, both in terms of the hydrophobicity of the host and of the guest. Our findings show that small changes that reduce the host hydrophobic surface area without reducing either the number of negative charges or amount of aromatic surface area are found to significantly decrease binding. Additionally, the position of solubilizing charges is also shown to influence the preferred host geometry and resulting binding constants.
- Whiting, Amanda L.,Hof, Fraser
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- Acylated flavonoid glycosides and accompanying phenolics from licorice
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Fifteen phenolic compounds including eight new flavonoid glycosides were isolated from Tohoku licorice (a kind of commercial licorice, which is regarded as the underground part of Glycyrrhiza uralensis). The structures of the new compounds (3R)-vestitol 7-O-glucoside and acylated flavonoid glycosides (licorice-glycosides A, B, C1, C2, D1, D2 and E), were elucidated. The 1H NMR and CD spectral data of the acylated chalcone apioglucosides suggested the existence of intramolecular stacking of the feruloyl or p-coumaroyl groups over the aglycone residue.
- Hatano, Tsutomu,Takagi, Miyuki,Ito, Hideyuki,Yoshida, Takashi
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- Palladium-catalyzed tandem C,N-arylation of immobilized enamine for solid phase indole synthesis
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Intramolecular palladium-catalyzed N-arylation of immobilized dehydrohalophenylalaninate was found to proceed smoothly to form indolecarboxylates. The method was successfully combined with the Heck reaction to perform one pot indole synthesis via palladium-catalyzed tandem C,N-arylation reactions.
- Yamazaki, Kazuo,Nakamura, Yosuke,Kondo, Yoshinori
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- Synthesis of Indoles by Reductive Cyclization of Nitro Compounds Using Formate Esters as CO Surrogates
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Alkyl and aryl formate esters were evaluated as CO sources in the Pd- and Pd/Ru-catalyzed reductive cyclization of 2-nitrostyrenes to give indoles. Whereas the use of alkyl formates requires the presence of a ruthenium catalyst such as Ru3(CO)12, the reaction with phenyl formate can be performed by using a Pd/phenanthroline complex alone. Phenyl formate was found to be the most effective CO source and the desired products were obtained in excellent yields, often higher than those previously reported using pressurized CO. The reaction tolerates many functional groups, including sensitive ones like a free aldehydic group or a pendant pyrrole. Detailed experiments and kinetic studies allow to conclude that the activation of phenyl formate is base-catalyzed and that the metal doesn't play a role in the decarbonylation step. The reactions can be performed in a single thick-walled glass tube with as little as 0.2 mol-% palladium catalyst and even on a 2 g scale. The same protocol can be extended to other nitro compounds, affording different heterocycles.
- Ahmed Fouad, Manar,Ferretti, Francesco,Formenti, Dario,Milani, Fabio,Ragaini, Fabio
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supporting information
p. 4876 - 4894
(2021/09/20)
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- Improved preparation method of indole-2-formic acid as starting material of perindopril
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The invention discloses an improved preparation method of indole-2-formic acid by using perindopril as a starting raw material, which comprises the following steps: S1, taking 2-bromobenzaldehyde and ethyl acetate as raw materials, under the action of sodium ethoxide, carrying out Claisen-Schmidt condensation reaction to synthesize ethyl 2-bromocinnamate; s2, carrying out cyclization reaction on the ethyl 2-bromocinnamate in an amide solvent by using cuprous halide as a coupling catalyst and sodium azide as a nitrogen source to synthesize the indole-2-formic acid in one pot. According to the invention, 2-bromobenzaldehyde is used as a raw material for preparation, ethyl 2-bromocinnamate is firstly prepared, then cuprous halide is used as a coupling catalyst, sodium azide is used as a nitrogen source, cyclization reaction is carried out in an amide solvent, indole-2-formic acid is synthesized in one pot, and the HPLC content is 99% or above.
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Paragraph 0039-0049
(2021/07/10)
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- Synthesis and antibacterial evaluation of (E)-1-(1H-indol-3-yl) ethanone O-benzyl oxime derivatives against MRSA and VRSA strains
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Infections caused due to multidrug resistant organisms have emerged as a constant menace to human health. Even though numerous antibiotics are currently available for treating infectious diseases, a great number of bacterial strains have acquired resistance to many of them. Among these, infections caused due to Staphylococcus aureus are predominant in adult and paediatric population. Indole is a prominent chemical scaffold found in many pharmacologically active natural products and synthetic drugs. A number of oxime ether containing compounds have attracted attention of researchers owing to their interesting biological properties. Current work details the synthesis of indole containing oxime ether derivatives and their evaluation for antimicrobial activity against a panel of bacterial and mycobacterial strains. Synthesized compounds demonstrated good to moderate activity against drug-resistant S. aureus including resistant to vancomycin. Among all, compound 5h was found to possess potent activity against susceptible as well as MRSA and VRSA strains of S. aureus with MIC of 1 μg/mL and 2–4 μg/mL respectively. In addition, compound 5h was found to be non-toxic to Vero cells and exhibited good selectivity index of >40. Further, 5h, E-9a and E-9b possessed good biofilm inhibition against S. aureus. With these assuring biological properties, synthesized compounds could be potential prospective antimicrobial agents.
- Akunuri, Ravikumar,Veerareddy, Vaishnavi,Kaul, Grace,Akhir, Abdul,Unnissa, Tanveer,Parupalli, Ramulu,Madhavi,Chopra, Sidharth,Nanduri, Srinivas
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supporting information
(2021/08/27)
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- FLOW CHEMISTRY SYNTHESIS OF ISOCYANATES
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The disclosure provides, inter alia, safe and environmentally-friendly methods, such as flow chemistry, to synthesize isocyanates, such as methylene diphenyl diisocyanate, toluene diisocyanate, hexamethylene diisocyanate, isophorone diisocyanate, and tetramethylxylene diisocyanate.
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Paragraph 0175; 0186-0187; 0261-0262
(2021/06/22)
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- Pd-Catalyzed Reductive Cyclization of Nitroarenes with CO2 as the CO Source
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A reductive amination process that constructs indoles, carbazoles or benzimidazoles from nitroarenes – irrespective of their electronic or steric nature – was developed that uses CO2 as the source of CO. The process is robust, tolerating common gaseous components of flue gas (H2S, SO2, NO and H2O) without adversely affecting the reductive cyclization.
- Guan, Xinyu,Zhu, Haoran,Zhao, Yingwei,Driver, Tom G.
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supporting information
p. 57 - 60
(2019/12/11)
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- Rh/TiO2-Photocatalyzed Acceptorless Dehydrogenation of N-Heterocycles upon Visible-Light Illumination
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TiO2 is an effective and extensively employed photocatalyst, but its practical use in visible-light-mediated organic synthesis is mainly hindered by its wide band gap energy. Herein, we have discovered that Rh-photodeposited TiO2 nanoparticles selectively dehydrogenate N-heterocyclic amines with the concomitant generation of molecular hydrogen gas in an inert atmosphere under visible light (λmax = 453 nm) illumination at room temperature. Initially, a visible-light-sensitive surface complex is formed between the N-heterocycle and TiO2. The acceptorless dehydrogenation of N-heterocycles is initiated by direct electron transfer from the HOMO energy level of the amine via the conduction band of TiO2 to the Rh nanoparticle. The reaction condition was optimized by examining different photodeposited noble metals on the surface of TiO2 and solvents, finding that Rh0 is the most efficient cocatalyst, and 2-propanol is the optimal solvent. Structurally diverse N-heterocycles such as tetrahydroquinolines, tetrahydroisoquinolines, indolines, and others bearing electron-deficient as well as electron-rich substituents underwent the dehydrogenation in good to excellent yields. The amount of released hydrogen gas evinces that only the N-heterocyclic amines are oxidized rather than the dispersant. This developed method demonstrates how UV-active TiO2 can be employed in visible-light-induced synthetic dehydrogenation of amines and simultaneous hydrogen storage applications.
- Bahnemann, Detlef W.,Balayeva, Narmina O.,Dillert, Ralf,Mamiyev, Zamin,Zheng, Nan
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p. 5542 - 5553
(2020/08/25)
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- Protocol for Visible-Light-Promoted Desulfonylation Reactions Utilizing Catalytic Benzimidazolium Aryloxide Betaines and Stoichiometric Hydride Donor Reagents
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An unprecedented photocatalytic system consisting of benzimidazolium aryloxide betaines (BI+-ArO-) and stoichiometric hydride reducing reagents was developed for carrying out desulfonylation reactions of N-sulfonyl-indoles,-amides, and-amines, and α-sulfonyl ketones. Measurements of absorption spectra and cyclic voltammograms as well as density functional theory (DFT) calculations were carried out to gain mechanistic information. In the catalytic system, visible-light-activated benzimidazoline aryloxides (BIH-ArO-), generated in situ by hydride reduction of the corresponding betaines BI+-ArO-, donate both an electron and a hydrogen atom to the substrates. A modified protocol was also developed so that a catalytic quantity of more easily prepared hydroxyaryl benzimidazolines (BIH-ArOH) is used along with a stoichiometric hydride donor to promote the photochemical desulfonylation reactions.
- Hasegawa, Eietsu,Tanaka, Tsukasa,Izumiya, Norihiro,Kiuchi, Takehiro,Ooe, Yuuki,Iwamoto, Hajime,Takizawa, Shin-Ya,Murata, Shigeru
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p. 4344 - 4353
(2020/04/09)
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- Design and synthesis of thiadiazolo-carboxamide bridged β-carboline-indole hybrids: DNA intercalative topo-IIα inhibition with promising antiproliferative activity
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The conjoining of salient pharmacophoric properties directing the development of prominent cytotoxic agents was executed by constructing thiadiazolo-carboxamide bridged β-carboline-indole hybrids. On the evaluation of in vitro cytotoxic potential, 12c exhibited prodigious cytotoxicity among the synthesized new molecules 12a–k, with an IC50 50 value of 2.82 ± 0.10 μM. Besides, another compound 12a also displayed impressive cytotoxicity against A549 cell line (IC50: 3.00 ± 1.40 μM). Further target-based assay of these two compounds 12c and 12a revealed their potential as DNA intercalative topoisomerase-IIα inhibitors. Additionally, the antiproliferative activity of compound 12c was measured in A549 cells by traditional apoptosis assays revealing the nuclear, morphological alterations, and depolarization of membrane potential in mitochondria and externalization of phosphatidylserine in a concentration-dependent manner. Cell cycle analysis unveiled the G0/G1 phase inhibition and wound healing assay inferred the inhibition of in vitro cell migration by compound 12c in lung cancer cells. Remarkably, the safety profile of compound 12c was disclosed by screening against normal human lung epithelial cell line (BEAS-2B: IC50: 71.2 ± 7.95 μM) with a selectivity index range of 14.9–25.26. Moreover, Molecular modeling studies affirm the intercalative binding of compound 12c and 12a in the active pocket of topo-IIα. Furthermore, in silico prediction of physico-chemical parameters divulged the propitious drug-like properties of the synthesized derivatives.
- Tokala, Ramya,Sana, Sravani,Lakshmi, Uppu Jaya,Sankarana, Prasanthi,Sigalapalli, Dilep Kumar,Gadewal, Nikhil,Kode, Jyoti,Shankaraiah, Nagula
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- Synthesis of pyrrolocarbazoles with N-substituted alkynyl-, alkylcyano- And alkylhydroxyl-groups
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Due to their involvement in almost all stages of cellular life, kinase biomolecular catalysts have been linked to cancer development and, thus, remain attractive drug targets for cancer therapeutics. 6-(3-Hydroxypropyl)-, 6-(2-hydroxyethyl)-, 6-(2-propynyl)- and 6-(3’-propanenitrile)-pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were synthesized as potential small molecule EGFR kinase inhibitors. The pyrrolocarbazole compounds were synthesized by way of a Diels-Alder approach involving N-alkylated 2-vinyl-1H-indole and maleimide as starting materials followed by aromatization with MnO2.
- van der Westhuyzen, Alet E.,Hadjegeorgiou, Kathy,Green, Ivan R.,Pelly, Stephen C.,van Otterlo, Willem A.L.
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p. 129 - 147
(2021/01/20)
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- New isatin–indole conjugates: Synthesis, characterization, and a plausible mechanism of their in vitro antiproliferative activity
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Background: Cancer remains the leading cause of human morbidity universally. Hence, we sought to assess the in vitro antiproliferative activity of new isatin-based conjugates (5a–s) against three human cancer cell lines. Methods: The antiproliferative activities of compounds 5a–s were evaluated in vitro and their ADME (absorption, distribution, metabolism and excretion) was carried out using standard protocols. Subsequently, Western blot analysis was conducted to elucidate the potential antiproliferative mechanism of compounds 5a–s. Results: The in vitro antiproliferative activities of compounds 5a–s against the tested cancer cell lines ranged from 20.3 to 95.9%. Compound 5m had an IC50 value of 1.17 μM; thus, its antiproliferative potency was approximately seven-fold greater than that of sunitinib (IC50 = 8.11 μM). In-depth pharmacological testing was conducted with compound 5m to gain insight into the potential antiproliferative mechanism of this class of compounds. Compound 5m caused an increase in the number of cells in the G1 phase, with a concomitant reduction of those in the G2/M and S phases. Additionally, compound 5m significantly and dose-dependently reduced the amount of phosphorylated retinoblastoma protein detected. Compound 5m enhanced expression of B cell translocation gene 1, cell cycle-associated proteins (cyclin B1, cyclin D1, and phosphorylated cyclin-dependent kinase 1), and a pro-apoptotic protein (Bcl-2-associated X protein gene), and activated caspase-3. ADME predictions exposed the oral liability of compounds 5a-s. Conclusion: Herein, we revealed the antiproliferative activity and ADME predictions of the newly-synthesized compounds 5a–s and provided a detailed insight into the pharmacological profile of compound 5m. Thus, compounds 5a–s can potentially be exploited as new antiproliferative lead compounds for cancer chemotherapeutic.
- Al-Wabli, Reem I.,Almomen, Aliyah A.,Almutairi, Maha S.,Attia, Mohamed I.,Keeton, Adam B.,Piazza, Gary A.
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p. 483 - 495
(2020/02/20)
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- A Bu4N[Fe(CO)3(NO)]-Catalyzed Hemetsberger–Knittel Indole Synthesis
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The nucleophilic Fe complex Bu4N[Fe(CO)3(NO)] (TBA[Fe]) catalyzes the direct intramolecular amination of aryl vinyl azides to give the corresponding indole derivatives in good to excellent yields.
- Baykal, Aslihan,Plietker, Bernd
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supporting information
(2020/02/20)
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- Intramolecular Pd-catalyzed reductive amination of enolizable sp3-C-H bonds
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A palladium-catalyzed reductive cyclization of nitroarenes has been designed to construct sp3-C-NHAr bonds from sp3-C-H bonds by using an enolizable nucleophile to intercept a nitrosoarene intermediate. Exposure of ortho-substituted nitroarenes to 5 mol ?% of Pd(OAc)2 and 10 mol ?% of phenanthroline under 2 atm of CO constructs partially saturated 5-, 6-, or 7-membered N-heterocycles using α-pyridyl carboxylates, malonates, 1,3-dimethylbarbituric acid, 1,3-diones, or difurans as the nucleophile.
- Ford, Russell L.,Alt, Isabel,Jana, Navendu,Driver, Tom G.
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p. 8827 - 8831
(2019/10/28)
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- Divergent synthesis of indole-2-carboxylic acid derivatives via ligand-free copper-catalyzed ullmann coupling reaction
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— This article describes a ligand-free copper-catalyzed Ullmami coupling reaction for the preparation of divergent indole-2-carboxylic acid derivatives including esters, amides and anhydrides. Various compounds 3, which could be synthesized from aldehydes conveniently, were used as substrate to provide the corresponding indole-2-carboxylic acid derivatives in moderate to good vields.
- Zhou, Jiadi,Chen, Yongjian,Huang, Junsong,Li, Jianjun
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p. 904 - 915
(2019/08/21)
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- Calcium-Catalyzed Formal [5 + 2] Cycloadditions of Alkylidene β-Ketoesters with Olefins: Chemodivergent Synthesis of Highly Functionalized Cyclohepta[ b]indole Derivatives
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The calcium-catalyzed, formal [5 + 2] cycloaddition of indolyl alkylidene β-ketoesters with mono- A nd disubstituted aryl olefins to form cyclohepta[b]indole derivatives has been established. Unanticipated chemodivergence with phenyl vinyl sulfide/ether revealed a double [5 + 2] cycloaddition cascade providing ethano-bridged cyclohepta[b]indoles. Overall, the method's highlights include: (1) use of a green, calcium-based catalyst (2.5 mol % loading); (2) reaction times under 1 h; (3) mild reaction conditions; (4) substrate-derived chemodivergence; (5) functional group tolerance; and (6) examples of derivatization.
- Parker, Ariel N.,Martin, M. Cynthia,Shenje, Raynold,France, Stefan
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supporting information
p. 7268 - 7273
(2019/10/08)
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- Palladium(0)-Catalyzed Intermolecular Asymmetric Cascade Dearomatization Reaction of Indoles with Propargyl Carbonate
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An intermolecular asymmetric cascade dearomatization reaction of indole derivatives with propargyl carbonate was developed. The challenges associated with both the chemoselectivity between the carbon and nitrogen nucleophile and the enantioselective control during the formation of an all-carbon quaternary stereogenic center were well addressed by a Pd catalytic system derived from the Feringa ligand. A series of enantioenriched multiply substituted fused indolenines were provided in good yields (71–86 %) with excellent enantioselectivity (91–96 % ee) and chemoselectivity (3/4>19:1 in most cases).
- Ding, Lu,Gao, Run-Duo,You, Shu-Li
-
supporting information
p. 4330 - 4334
(2019/02/25)
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- Synthesis of N-Heterocycles by Reductive Cyclization of Nitro Compounds using Formate Esters as Carbon Monoxide Surrogates
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A series of alkyl and aryl formate esters were evaluated as CO sources in the Pd- and Pd/Ru-catalyzed reductive cyclization of substituted nitro compounds to afford heterocycles, especially indoles. Phenyl formate was found to be the most effective, and it allowed the desired products to be obtained in excellent yields, often higher than those previously reported with pressurized CO. Through detailed experiments and kinetic studies, we were able to discern between metal-catalyzed and base-mediated activation of phenyl formate and confirmed that just the base was effective in catalyzing its decarbonylation.
- Formenti, Dario,Ferretti, Francesco,Ragaini, Fabio
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p. 148 - 152
(2017/12/04)
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- A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid derivatives and indoles based on the Reissert reaction
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The formation of 3-(2-nitrophenyl)pyruvic acid and its amide and ester derivatives – key compounds for the Reissert indole synthesis – was achieved under various reaction conditions via the acid catalyzed hydrolysis of 5-(2-nitrobenzyliden)-2,2-dimethyl-1,3-oxazolidin-4-one, which is readily available from 3-(2-nitrophenyl)oxirane-2-carboxamide. A new and highly efficient method for the synthesis of indole-2-carboxylic acid derivatives via the intramolecular reductive cyclization of o-nitrophenylpyruvic acid and its amide and ester derivatives was developed using Na2S2O4 in dioxane/water at reflux.
- Mamedov, Vakhid A.,Mamedova, Vera L.,Syakaev, Victor V.,Khikmatova, Gul'naz Z.,Korshin, Dmitry E.,Kushatov, Temur A.,Latypov, Shamil K.
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p. 3923 - 3925
(2018/10/02)
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- Asymmetric Nazarov Cyclizations Catalyzed by Chiral-at-Metal Complexes
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The application of Lewis acidic chiral-at-metal complexes of iridium(III) and rhodium(III) as catalysts for the asymmetric polarized Nazarov cyclization of dihydropyran- and indole-functionalized α-unsaturated β-ketoesters is reported (overall 24 examples). For both substrate classes, catalyst loadings of 2 mol% were found to be sufficient for achieving high yields and high stereoselectivities. The cyclized dihydropyran products were isolated in 85–98% yield, with 89%–>99% ee, and trans/cis ratios of 15:1–50:1 (9 examples). The cyclized indole products were typically isolated in more than 70% yield and in up to 93% yield, typically with more than 90% ee and in up to 97% ee, and trans/cis ratios of 12:1–28:1 (15 examples). (Figure presented.).
- Mietke, Thomas,Cruchter, Thomas,Larionov, Vladimir A.,Faber, Tabea,Harms, Klaus,Meggers, Eric
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supporting information
p. 2093 - 2100
(2018/04/19)
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- Benzimidazolium Naphthoxide Betaine Is a Visible Light Promoted Organic Photoredox Catalyst
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Benzimidazolium naphthoxide (-ONap-BI+) was first synthesized and utilized as an unprecedented betaine photoredox catalyst. Photoexcited state of -ONap-BI+ generated by visible light irradiation catalyzes the reductive deiodination as well as desulfonylation reactions in which 1,3-dimethyl-2-phenylbenzimidazoline (Ph-BIH) cooperates with as an electron and hydrogen atom donor. Significant solvent effects on the reaction progress were discovered, and specific solvation toward imidazolium and naphthoxide moieties of -ONap-BI+ was proposed.
- Hasegawa, Eietsu,Izumiya, Norihiro,Miura, Tomoaki,Ikoma, Tadaaki,Iwamoto, Hajime,Takizawa, Shin-Ya,Murata, Shigeru
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p. 3921 - 3927
(2018/04/14)
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- Visible Light and Hydroxynaphthylbenzimidazoline Promoted Transition-Metal-Catalyst-Free Desulfonylation of N-Sulfonylamides and N-Sulfonylamines
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A visible light promoted process for desulfonylation of N-sulfonylamides and -amines has been developed, in which 1,3-dimethyl-2-hydroxynaphthylbenzimidazoline (HONap-BIH) serves as a light absorbing, electron and hydrogen atom donor, and a household white light-emitting diode serves as a light source. The process transforms various N-sulfonylamide and -amine substrates to desulfonylated products in moderate to excellent yields. The observation that the fluorescence of 1-methyl-2-naphthoxy anion is efficiently quenched by the substrates suggests that the mechanism for the photoinduced desulfonylation reaction begins with photoexcitation of the naphthoxide chromophore in HONap-BIH, which generates an excited species via intramolecular proton transfer between the HONap and BIH moieties. This process triggers single electron transfer to the substrate, which promotes loss of the sulfonyl group to form the free amide or amine. The results of studies employing radical probe substrates as well as DFT calculations suggest that selective nitrogen-sulfur bond cleavage of the substrate radical anion generates either a pair of an amide or amine anion and a sulfonyl radical or that of an amidyl or aminyl radical and sulfinate anion, depending on the nature of the N-substituent on the substrate. An intermolecular version of this protocol, in which 1-methyl-2-naphthol and 1,3-dimethyl-2-phenylbenzimidazoline are used concomitantly, was also examined.
- Hasegawa, Eietsu,Nagakura, Yuto,Izumiya, Norihiro,Matsumoto, Keisuke,Tanaka, Tsukasa,Miura, Tomoaki,Ikoma, Tadaaki,Iwamoto, Hajime,Wakamatsu, Kan
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p. 10813 - 10825
(2018/07/30)
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- Gold(0) catalyzed dehydrogenation of N-heterocycles
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Gold nanoclusters are good catalyst precursors for the catalytic dehydrogenation of indolines, tetrahydroquinazolines, and related N-heterocycles. The catalytically active species is presumably Au(0) nanoparticles.
- Kumaran, Elumalai,Leong, Weng Kee
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supporting information
p. 3958 - 3960
(2018/10/02)
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- Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach
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Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3′,4′,5′-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC50 values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3′,4′,5′-trimethoxyphenyl)-2-propen-1-one framework. The structure–activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC50 values of 0.37, 0.16 and 0.17 μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC50: 18 μM). This derivative also displayed cytotoxic properties (IC50 values ~1 μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G2-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3′,4′,5′-trimethoxyphenyl scaffold.
- Preti, Delia,Romagnoli, Romeo,Rondanin, Riccardo,Cacciari, Barbara,Hamel, Ernest,Balzarini, Jan,Liekens, Sandra,Schols, Dominique,Estévez-Sarmiento, Francisco,Quintana, José,Estévez, Francisco
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p. 1225 - 1238
(2018/09/04)
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- Continuous flow synthesis of indoles by Pd-catalyzed deoxygenation of 2-nitrostilbenes with carbon monoxide
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The palladium-catalyzed deoxygenation of o-vinylnitrobenzenes employing carbon monoxide as a terminal reductant produces indoles in a continuous flow environment. The reaction proceeds with catalyst loadings of 1 to 2 mol% Pd(OAc)2 in the presence of suitable ligands/additives and generates carbon dioxide as the only stoichiometric side-product. The reductive cyclization proceeds in a clean fashion with high initial reaction rates in the pressurized flow reactor, ultimately leading to deposition of catalytically inactive palladium(0) inside the channels of the flow device, allowing for an efficient catalyst recovery. A variety of o-vinylnitrobenzenes (o-nitrostilbenes and -styrenes) were converted to the corresponding indoles within 15 to 30 min at a reaction temperature of 140 °C to furnish products in good to excellent yields (10-20 bar CO pressure). Mechanistic aspects and the scope of the transformation are discussed.
- Glotz, Gabriel,Gutmann, Bernhard,Hanselmann, Paul,Kulesza, Anna,Roberge, Dominique,Kappe, C. Oliver
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p. 10469 - 10478
(2017/02/15)
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- Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor
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A cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated directly using an electric current and is capable of rapidly delivering temperatures and pressures up to 400 °C and 200 bar, respectively. High-temperature and high-pressure applications of this reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 and 400 °C with excellent conversions and good to excellent isolated product yields. Examples of Diels-Alder reactions were also carried out at temperatures up to 300 °C in high yield. No additives or catalysts were used in the reactions.
- Adeyemi, Ahmed,Bergman, Joakim,Br?nalt, Jonas,S?vmarker, Jonas,Larhed, Mats
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supporting information
p. 947 - 955
(2017/07/26)
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- A double-indole hydrazone compound and use thereof
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The invention provides a bisindole acylhydrazone compound shown as the formula I or salt, hydrate or crystals, accepted in the pharmacy, of the bisindole acylhydrazone compound. According to the bisindole acylhydrazone compound, R does not exist or is selected from alkylene of C1-5. The bisindole acylhydrazone compound has a certain antibacterial activity, and can serve as potential antibiotics or a daily chemical product. What is beyond the expectation is that compounds 4e-4h and compounds 4a-4c are quite similar in structure, the antibacterial activity of the compounds 4e-4h and the antibacterial activity of the compounds 4a-4c are obviously better than that of other compounds, particularly, the activity of the compound 4h is best and is remarkably better than that of compounds 4e-4g. The formula I is shown in the specification.
- -
-
Paragraph 0036; 0039-0040
(2017/10/06)
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- A double-indole hydrazone compound and its salt (by machine translation)
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The present invention provides a bis-indole compounds shown as formula I hydrazone compound or its pharmaceutically acceptable salt, hydrate or crystalline form. Wherein R is selected from none or C1 - 3 alkylene. This invention discovers, the present invention provides compound has antibacterial activity, can be used as a potential antibacterial drug or of daily use. It is not expected to, compound 4 d with a compound 4a - 4c structure is extremely similar, but its antibacterial activity is obviously superior to other compound; and, compound 4 d to Staphylococcus aureus bacteriostatic activity to be improved to the role of the Escherichia coli, note compound 4 d to Staphylococcus aureus more sensitive, if the use of the compound of antibacterial, in limited under the dosage, more easily targeted inhibit specific bacteria (such as jin pujun), to avoid other bacteria produce unnecessary drug resistance. (by machine translation)
- -
-
Paragraph 0032-0038
(2017/10/06)
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- Total synthesis and structural revision of a mangrove alkaloid
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We report the total synthesis of an alkaloid isolated from the mangrove fungi Hypocrea virens, based on the originally claimed structure, via a photochemical sequence. Inconsistencies between data sets led to a revision of the proposed structure followed by a concise synthetic sequence to deliver the revised natural product.
- Green, Michael T.,Peczkowski, Gary R.,Al-Ani, Aneesa J.,Benjamin, Sophie L.,Simpkins, Nigel S.,Jones, Alan M.
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p. 48754 - 48758
(2017/11/06)
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- Indole hydrazone compounds
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The invention provides a compound of the formula I as shown in the description. In the formula, R is connected with the carbon atom at the 2nd or 3rd site of indolyl and is selected from none or C1-3 alkylene. Molecular tweezers of bisindole acylhydrazone have a good recognition cooperation function on inspected malic acid, tartaric acid, ascorbic acid and tryptophan, and have no recognition cooperation function on other inspected organic acids such as lactic acid, oxalic acid, tyrosine, histidine and serine. Therefore, due to the selective recognition property of a molecular tweezers receptor has the potential to be applied to fields such as analysis and separation of relevant organic acids in biological medicines, and transportation of organic acid medicines.
- -
-
Paragraph 0039-0042
(2017/11/17)
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- Visible light-promoted reductive transformations of various organic substances by using hydroxyaryl-substituted benzimidazolines and bases
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Visible light promoted reduction reactions of organohalides, sulfonamides, organonitriles and epoxy ketones were performed using 1,3-dimethylbenzimidazolines possessing 2-hydroxynaphthyl or 2-hydroxyphenyl substituents (HOAr-DMBIH) as photo-reductants. Xe or Hg–Xe lamp through an appropriate glass-filter (λ>390 nm) and a household white light-emitting diode were used as light sources. In these reactions, reductive cleavages of carbon[sbnd]halogen, nitrogen[sbnd]sulfur, carbon[sbnd]carbon (nitrile) and carbon[sbnd]oxygen bonds take place. Bases exert significant effects on the progress of these reactions in a manner that depends on the nature of the substrate. Addition of 1,8-diazabicyclo[5.4.0]undec-7-ene as well as potassium t-butoxide significantly accelerates photo-reduction reactions of organohalides, sulfonamides and organonitriles while the decomposition of formed hydroxy ketones occurs in reactions of epoxy ketones. Single electron transfer from the photo-excited states of benzimidazolines (HOAr-DMBIH) or their deprotonated analogues (?OAr-DMBIH) to the substrates is proposed to initiate these reactions.
- Hasegawa, Eietsu,Izumiya, Norihiro,Fukuda, Takuya,Nemoto, Kazuki,Iwamoto, Hajime,Takizawa, Shin-ya,Murata, Shigeru
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p. 7805 - 7812
(2016/11/17)
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- Aerobic copper-catalyzed decarboxylative thiolation
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Copper-catalyzed decarboxylative thiolation using molecular oxygen as the sole oxidant was developed. A variety of aromatic carboxylic acids including 2-nitrobenzoic acids, pentafluorobenzoic acid and several heteroaromatic carboxylic acids undergo efficient thiolation to furnish the aryl sulfides in moderate to excellent yields.
- Li, Minghao,Hoover, Jessica M.
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supporting information
p. 8733 - 8736
(2016/07/15)
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- Direct Tryptophols Synthesis from 2-Vinylanilines and Alkynes via C - C Triple Bond Cleavage and Dioxygen Activation
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An unexpected metal-free C - C triple bond cleavage, dioxygen activation, and reassembly into tryptophol derivatives has been developed. This chemistry provides a novel, simple, and efficient approach to highly valuable tryptophol derivatives from simple substrates under mild conditions. The mechanistic studies may promote the discovery of new methodologies through C-C bond cleavage and dioxygen activation.
- Shen, Tao,Zhang, Yiqun,Liang, Yu-Feng,Jiao, Ning
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p. 13147 - 13150
(2016/10/24)
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- Iron-Catalyzed Intramolecular C(sp2)-H Amination
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The nucleophilic iron complex Bu4N[Fe(CO)3(NO)] (TBA[Fe]) catalyzes the direct intramolecular C-H amination of α-azidobiaryls and (azidoaryl)alkenes into the corresponding carbazoles and indoles, respectively, under mild conditions and with low catalyst loadings. These features and the broad functional-group tolerance render this method a particularly attractive alternative to established noble-metal-based procedures.
- Alt, Isabel T.,Plietker, Bernd
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p. 1519 - 1522
(2016/02/14)
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- Flexible synthesis of isomeric pyranoindolones and evaluation of cytotoxicity towards HeLa cells
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A hybrid pharmacophore approach for the synthesis of isomeric pyranoindolones was achieved by employing gold(III) chloride-catalyzed cycloisomerization of alkyne-tethered indole carboxylic acids in good to excellent yield. All the synthesized compounds were evaluated for their tumor cell growth inhibitory activity against human cervix adenocarcinoma (HeLa) which revealed that three compounds exhibited activity comparable with the standard cis-platin (IC50 = 0.08 μM). Molecular docking of all the compounds in Vaccinia H1-Related (VHR) Phosphatase receptor also supported that compound 7d as the most active with a free energy of binding as ?8.27 kcal/mol. [Figure not available: see fulltext.]
- Jeyaveeran,Praveen, Chandrasekar,Arun,Prince,Perumal
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p. 787 - 802
(2016/05/19)
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- Aryl-substituted dimethylbenzimidazolines as effective reductants of photoinduced electron transfer reactions
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Photoinduced electron transfer (PET) reactions promoted by 2-aryl substituted 1,3-dimethylbenzimidazolines (Ar-DMBIH) were investigated. Excited states of Ar-DMBIH, formed by irradiation using light above 360 nm, initiate PET reductions of various organic substrates, including transformations of epoxy ketones to aldols, free radical rearrangements such as the Dowd-Beckwith ring-expansion and 5-exo hexenyl cyclization, deprotection of N-sulfonyl-indols, and allylation of acyl formates. In these processes, Ar-DMBIH possessing 1-naphthyl, 2-naphthyl, 1-pyrenyl and 9-anthryl substituents formally act as two electron and one proton donors while the hydroxynaphthyl substituted derivative serves as a two electron and two proton donor. On the basis of the results of absorption spectroscopy studies, cyclic voltammetry and DFT calculation, a mechanistic sequence for these reduction reactions is proposed that involves initial photoexcitation of the aryl chromophore of the Ar-DMBIH followed by single electron transfer (SET) to the organic substrate to generate the radical cation of benzimidazoline and the radical anion of the substrate.
- Hasegawa, Eietsu,Ohta, Taku,Tsuji, Shiori,Mori, Kazuma,Uchida, Ken,Miura, Tomoaki,Ikoma, Tadaaki,Tayama, Eiji,Iwamoto, Hajime,Takizawa, Shin-Ya,Murata, Shigeru
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p. 5494 - 5505
(2015/08/03)
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- A porous metal-organic cage constructed from dirhodium paddle-wheels: Synthesis, structure and catalysis
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Self-assembly of dirhodium(ii) tetraacetate (Rh2(OAc)4) with a dicarboxylic acid 3,3′-(1,3-phenylenebis(ethyne-2,1-diyl))dibenzoic acid (H2pbeddb) gives rise to a metal-organic cage (MOC) containing Rh-Rh bonds with the formula of [Rh4(pbeddb)4(H2O)2(DMAC)2] (MOC-Rh-1). Single-crystal X-ray diffraction analysis reveals that MOC-Rh-1 shows a lantern-type cage structure, in which a pair of Rh2(CO2)4 paddlewheels is linked by four diacid ligands. The dimensions of the inner cavity of MOC-Rh-1 are 9.5 × 14.8 ?2 (atom-to-atom distances across opposite metal and phenyl groups of pbeddb2-). In the solid phase, the cages are aligned by π-π stacking to form one-dimensional channels (9.5 × 11.1 ?2) through cage windows. Therefore, the crystalline samples of MOC-Rh-1 are porous with the inner and outer cavities of the cages accessible under the heterogeneous condition. MOC-Rh-1 has been fully characterized by EA, TGA, PXRD, IR, UV-vis and XPS measurements. The catalytic tests disclose that activated MOC-Rh-1 is effective in the intramolecular C-H amination of vinyl, dienyl and biaryl azides, leading to the formation of indoles, pyrroles and carbazoles, respectively, and the porous catalyst can be recycled easily and used for at least nine runs without significant loss of activity. In the nine runs, the conversions were in the range of 93-99%, whereas in the tenth run, the conversion was reduced to 78%.
- Chen, Lianfen,Yang, Tao,Cui, Hao,Cai, Tao,Zhang, Li,Su, Cheng-Yong
-
supporting information
p. 20201 - 20209
(2015/10/19)
-
- A practical, chemoselective approach to O-methylation of carboxylic acids with dimethyl malonate
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A practical and chemoselective method is described for the O-methylation of carboxylic acids. Dimethyl malonate, a low toxic and commercially available compound was found to be an effective methylating reagent for a variety of carboxylic acids affording methyl ester products in good to high yields and with excellent chemoselectivity, without the use of strong bases as additives. A mechanism involving the utilization of potassium bromide is tentatively proposed.
- Mao, Jincheng,Liu, Defu,Li, Yongming,Zhao, Jinzhou,Rong, Guangwei,Yan, Hong,Zhang, Guoqi
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p. 9067 - 9072
(2015/11/09)
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- [Fe(F20TPP)Cl]-catalyzed amination with arylamines and {[Fe(F20TPP)(NAr)](PhI=NAr)}+. Intermediate assessed by high-resolution ESI-MS and DFT calculations
-
Amination of C-H bonds catalyzed by transition metal complexes via nitrene/imide insertion is an appealing strategy for C-N bond formation, and the use of iminoiodinanes, or their in situ generated forms from 'PhI-(OAc)2 + primary amides (such as sulfonamides, sulfamates, and carbamates)', as nitrogen sources for the amination reaction has been well documented. In this work, a 'metal catalyst + PhI(OAc)2 + primary arylamines' amination protocol has been developed using [Fe(F20TPP)Cl] (H2F20TPP = meso-tetrakis(pentafluorophenyl)porphyrin) as a catalyst. This catalytic method is applicable for both intra- and intermolecular amination of sp2 and sp3 C-H bonds (> 27 examples), affording the amination products, including natural products such as rutaecarpine, in moderate-to-good yields. ESI-MS analysis and DFT calculations lend support for the involvement of {[Fe(F20TPP)(NC6H4-p-NO2)](PhI=NC6H4-p-NO2)}+. intermediate in the catalysis.
- Liu, Yungen,Chen, Guo-Qiang,Tse, Chun-Wai,Guan, Xianguo,Xu, Zheng-Jiang,Huang, Jie-Sheng,Che, Chi-Ming
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supporting information
p. 100 - 105
(2015/02/19)
-
- Reevaluation of the 2-nitrobenzyl protecting group for nitrogen containing compounds: An application of flow photochemistry
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Photochemistry under continuous flow conditions has many potential benefits for photochemical reactions that are problematic in batch. The 2-nitrobenzyl moiety is a photolabile protecting group for nitrogen. However, N-deprotection is generally impractical and, therefore, has not been extensively adopted. This Letter reports significant improvements in the N-deprotection of the 2-nitrobenzyl group through the application of continuous flow photolysis. This procedure was applied to a variety of substrates including indoles, indazoles, pyrazoles and secondary amines. Significant improvement in yield, reaction time and scalability was observed under continuous flow conditions.
- Wendell, Chloe I.,Boyd, Michael J.
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supporting information
p. 897 - 899
(2015/02/05)
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- Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand
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Recently, we have demonstrated that N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652) (1) adopts a bitopic pose at one protomer of a dopamine D2 receptor (D2R) dimer to negatively modulate the binding of dopamine at the other protomer. The 1H-indole-2-carboxamide moiety of 1 extends into a secondary pocket between the extracellular ends of TM2 and TM7 within the D2R protomer. To target this putative allosteric site, we generated and characterized fragments that include and extend from the 1H-indole-2-carboxamide moiety of 1. N-Isopropyl-1H-indole-2-carboxamide (3) displayed allosteric pharmacology and sensitivity to mutations of the same residues at the top of TM2 as was observed for 1. Using 3 as an "allosteric lead", we designed and synthesized an extensive fragment library to generate novel SAR and identify N-butyl-1H-indole-2-carboxamide (11d), which displayed both increased negative cooperativity and affinity for the D2R. These data illustrate that fragmentation of extended compounds can expose fragments with purely allosteric pharmacology.
- Mistry, Shailesh N.,Shonberg, Jeremy,Draper-Joyce, Christopher J.,Klein Herenbrink, Carmen,Michino, Mayako,Shi, Lei,Christopoulos, Arthur,Capuano, Ben,Scammells, Peter J.,Lane, J. Robert
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p. 6819 - 6843
(2015/09/22)
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- Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold
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G protein-coupled receptors (GPCRs) represent a biological target class of fundamental importance in drug therapy. The GPRC6A receptor is a newly deorphanized class C GPCR that we recently reported for the first allosteric antagonists based on the 2-arylindole privileged structure scaffold (e.g., 1-3). Herein, we present the first structure-activity relationship study for the 2-arylindole antagonist 3, comprising the design, synthesis, and pharmacological evaluation of a focused library of 3-substituted 2-arylindoles. In a FRET-based inositol monophosphate (IP1) assay we identified compounds 7, 13e, and 34b as antagonists at the GPRC6A receptor in the low micromolar range and show that 7 and 34b display >9-fold selectivity for the GPRC6A receptor over related GPCRs, making 7 and 34b the most potent and selective antagonists for the GPRC6A receptor reported to date.
- Johansson, Henrik,Boesgaard, Michael Worch,N?rskov-Lauritsen, Lenea,Larsen, Inna,Kuhne, Sebastiaan,Gloriam, David E.,Br?uner-Osborne, Hans,Sejer Pedersen, Daniel
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p. 8938 - 8951
(2015/12/09)
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