- Molecular Structure and Photochemistry of (E)- and (Z)-Ethyl 3-(2-Indolyl)propenoate. Ground State Conformational Control of Photochemical Behavior and One-Way E -> Z Photoisomerization
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The molecular structure, electronic spectra, and photoisomerization of (E)- and (Z)-ethyl 3-(2-indolyl)propenoate, two methylated indole derivatives, and their N,N-dimethylamide analog have been investigated.The E ester exists in the ground state as a mixture of anti and syn rotational isomers.The spectroscopic and photochemical behaviors of the individual anti and syn conformers were characterized with the assistance of comparisons with the behavior of the methylated indole derivatives.The major anti conformer of the E ester absorbs and emits at shorter wavelength than the minor syn conformer.The rate constant for singlet state isomerization of the anti conformer is substantially larger than that of the syn conformer, resulting in a shorter singlet lifetime and smaller fluorescence quantum yield for the anti conformer.The behavior of the E amide in both the ground and excited states is similar to that of the ester.The Z isomers of the ester and amide possess a relatively strong intramolecular hydrogen bond.Their singlet states are weakly fluoroscent and photoisomerize ineffeciently in nonpolar solvents.Thus photostationary states highly enriched in the Z isomers are obtained in nonpolar solvents.The red-shifted, structureless emission observed upon irradiating the Z amide in an EPA or methylcyclohexane glass at 77 K is attributed to an excited state tautomer formed via intramolecular hydrogen transfer.
- Lewis, Frederick D.,Yang, Jye-Shane
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- Synthesis and evaluation of cyclic nitrone derivatives as potential anti-cancer agents
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Nitrones have been found to exhibit attractive biological values as immuno spin trapping agents. However, successful clinical cases of nitrone therapeutics are still lacking. Herein we report the synthesis and antiproliferative activity of a series of structurally diverse nitrone derivatives against a panel of 5 cancer cell lines, based on which indole- and pyrrole-fused were further evaluated by analogue preparation and in-vitro screening. Analogues with moderate to good potency were identified. This study shows the promise for further pursuit of nitrone-type small molecules in chemotherapy. [Figure not available: see fulltext.]
- Zhou, Wei,Ju, Dongyan,Ao, Yuhui,Liu, Yu,Zhao, Jinbo
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p. 1309 - 1316
(2021/05/27)
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- Potent Inhibition of Nicotinamide N-Methyltransferase by Alkene-Linked Bisubstrate Mimics Bearing Electron Deficient Aromatics
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Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (vitamin B3) to generate 1-methylnicotinamide (MNA). NNMT overexpression has been linked to a variety of diseases, most prominently human cancers, indicating its potential as a therapeutic target. The development of small-molecule NNMT inhibitors has gained interest in recent years, with the most potent inhibitors sharing structural features based on elements of the nicotinamide substrate and the S-adenosyl-l-methionine (SAM) cofactor. We here report the development of new bisubstrate inhibitors that include electron-deficient aromatic groups to mimic the nicotinamide moiety. In addition, a trans-alkene linker was found to be optimal for connecting the substrate and cofactor mimics in these inhibitors. The most potent NNMT inhibitor identified exhibits an IC50 value of 3.7 nM, placing it among the most active NNMT inhibitors reported to date. Complementary analytical techniques, modeling studies, and cell-based assays provide insights into the binding mode, affinity, and selectivity of these inhibitors.
- Buijs, Ned,Campagna, Roberto,Emanuelli, Monica,Gao, Yongzhi,Innocenti, Paolo,Jespers, Willem,Martin, Nathaniel I.,Parsons, Richard B.,Sartini, Davide,Van Haren, Matthijs J.,Van Westen, Gerard J. P.,Zhang, Yurui,Gutiérrez-De-Terán, Hugo
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p. 12938 - 12963
(2021/09/11)
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- Synthesis of 1-indolyl-3,5,8-substituted γ-carbolines: one-pot solvent-free protocol and biological evaluation
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1,5-Disubstituted indole-2-carboxaldehyde derivatives 1a–h and glycine alkyl esters 2a–c are shown to undergo a novel cascade imination-heterocylization in the presence of the organic base DIPEA to provide 1-indolyl-3,5,8-substituted γ-carbolines 3aa–ea in good yields. The γ-carbolines are fluorescent and exhibit anticancer activities against cervical, lung, breast, skin, and kidney cancer cells.
- Chelvam, Venkatesh,Dudhe, Premansh,Krishnan, Mena Asha,Pathak, Biswarup,Roy, Diptendu,Venkatasubbaiah, Krishnan,Yadav, Kratika
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supporting information
p. 1453 - 1463
(2021/07/02)
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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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- Amide-Amine Replacement in Indole-2-carboxamides Yields Potent Mycobactericidal Agents with Improved Water Solubility
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Indolecarboxamides are potent but poorly soluble mycobactericidal agents. Here we found that modifying the incipient scaffold by amide-amine substitution and replacing the indole ring with benzothiophene or benzoselenophene led to striking (10-20-fold) im
- Tan, Yu Jia,Li, Ming,Gunawan, Gregory Adrian,Nyantakyi, Samuel Agyei,Dick, Thomas,Go, Mei-Lin,Lam, Yulin
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supporting information
p. 704 - 712
(2020/11/30)
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- Au(I)-Catalyzed Pictet-Spengler Reactions All around the Indole Ring
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Au(I) complexes catalyze iso-Pictet-Spengler reactions. Ethylamine or methylamine chains were introduced at C2, C4, or the nitrogen atom of the indole ring, and the corresponding substrates were reacted in the presence of aldehydes and catalytic amounts of Au(I) complexes, leading to a variety of polycyclic scaffolds. Selectivity could be achieved in the course of a double iso-Pictet-Spengler reaction involving two successive aldehydes, leading to highly complex molecules.
- Milcendeau, Pierre,Zhang, Zhenhao,Glinsky-Olivier, Nicolas,Van Elslande, Elsa,Guinchard, Xavier
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p. 6406 - 6422
(2021/05/29)
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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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- Carbene-Catalyzed Enantioselective Aromatic N-Nucleophilic Addition of Heteroarenes to Ketones
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The aromatic nitrogen atoms of heteroarylaldehydes are activated by carbene catalysts to react with ketone electrophiles. Multi-functionalized cyclic N,O-acetal products are afforded in good to excellent yields and optical purities. Our reaction involves the formation of an unprecedented aza-fulvene-type acylazolium intermediate. A broad range of N-heteroaromatic aldehydes and electron-deficient ketone substrates works effectively in this transformation. Several of the chiral N,O-acetal products afforded through this protocol exhibit excellent antibacterial activities against Ralstonia solanacearum (Rs) and are valuable in the development of novel agrichemicals for plant protection.
- Liu, Yonggui,Luo, Guoyong,Yang, Xing,Jiang, Shichun,Xue, Wei,Chi, Yonggui Robin,Jin, Zhichao
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p. 442 - 448
(2019/11/25)
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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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- Visible-light assisted of nano Ni/g-C3N4 with efficient photocatalytic activity and stability for selective aerobic C?H activation and epoxidation
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A selective, economical, and ecological protocol has been described for the oxidation of methyl arenes and their analogs to the corresponding carbonyl compounds and epoxidation reactions of alkenes with molecular oxygen (O2) or air as a green oxygen source, under mild reaction conditions. The nano Ni/g-C3N4 exhibited high photocatalytic activity, stability, and selectivity in the C?H activation of methyl arenes, methylene arenes, and epoxidation of various alkenes under visible- light irradiation without the use of an oxidizing agent and under base free conditions.
- Akrami, Zahra,Hosseini-Sarvari, Mona
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supporting information
(2020/10/13)
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- Biocatalytic reduction of α,β-unsaturated carboxylic acids to allylic alcohols
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We have developed robust in vivo and in vitro biocatalytic systems that enable reduction of α,β-unsaturated carboxylic acids to allylic alcohols and their saturated analogues. These compounds are prevalent scaffolds in many industrial chemicals and pharmaceuticals. A substrate profiling study of a carboxylic acid reductase (CAR) investigating unexplored substrate space, such as benzo-fused (hetero)aromatic carboxylic acids and α,β-unsaturated carboxylic acids, revealed broad substrate tolerance and provided information on the reactivity patterns of these substrates. E. coli cells expressing a heterologous CAR were employed as a multi-step hydrogenation catalyst to convert a variety of α,β-unsaturated carboxylic acids to the corresponding saturated primary alcohols, affording up to >99percent conversion. This was supported by the broad substrate scope of E. coli endogenous alcohol dehydrogenase (ADH), as well as the unexpected CC bond reducing activity of E. coli cells. In addition, a broad range of benzofused (hetero)aromatic carboxylic acids were converted to the corresponding primary alcohols by the recombinant E. coli cells. An alternative one-pot in vitro two-enzyme system, consisting of CAR and glucose dehydrogenase (GDH), demonstrates promiscuous carbonyl reductase activity of GDH towards a wide range of unsaturated aldehydes. Hence, coupling CAR with a GDH-driven NADP(H) recycling system provides access to a variety of (hetero)aromatic primary alcohols and allylic alcohols from the parent carboxylates, in up to >99percent conversion. To demonstrate the applicability of these systems in preparative synthesis, we performed 100 mg scale biotransformations for the preparation of indole-3-aldehyde and 3-(naphthalen-1-yl)propan-1-ol using the whole-cell system, and cinnamyl alcohol using the in vitro system, affording up to 85percent isolated yield.
- Aleku, Godwin A.,Leys, David,Roberts, George W.
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p. 3927 - 3939
(2020/07/09)
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- TRICYCLIC COMPOUND AS CRTH2 INHIBITOR
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Provided are a tricyclic compound as shown in formula (I) as a CRTH2 inhibitor, or a pharmaceutically acceptable salt, a tautomer, a stereoisomer or a solvate thereof, and the use thereof in treating diseases related to CRTH2 receptors.
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- Addition of a Carbene Catalyst to Indole Aryl Aldehyde Activates a Remote δ-sp2 Carbon for Protonation and Formal [4+2] Reaction
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The addition of a carbene catalyst to an indole aryl aldehyde leads to the activation of a remote sp2 carbon that is five atoms away from the catalyst. The unsaturated Breslow intermediate formed between the catalyst and substrate undergoes an internal redox reaction and remote carbon protonation to generate an analogous azolium vinyl enolate intermediate. Subsequent [4+2] reaction with cyclic imine substrates eventually affords multicyclic pyridoindoles as nearly single diastereomers with excellent enantioselectivities.
- Zheng, Pengcheng,Wu, Shuquan,Mou, Chengli,Xue, Wei,Jin, Zhichao,Chi, Yonggui Robin
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p. 5026 - 5029
(2019/07/03)
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- Highly enantioselective synthesis of functionalized azepino[1,2-a] indoles via NHC-catalyzed [3+4] annulation
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The enantioselective [3+4] annulation of 3-formylindol-2-methyl-malonates with 2-bromoenals catalyzed by NHCs is described to afford functionalized azepino[1,2-a]indoles in high yields with excellent enantioselectivities. This method, in which the 3-formyl group in indoles acts as a necessary mediating group, provided cycloaddition products under mild conditions.
- Zhu, Shi-Ya,Zhang, Yuanzhen,Chen, Xin-Fa,Huang, Jun,Shi, Shi-Hui,Hui, Xin-Ping
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supporting information
p. 4363 - 4366
(2019/04/26)
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- Lewis Acid-Catalyzed Intramolecular [3 + 2] Cross-Cycloaddition of Donor- Acceptor Epoxides with Alkenes for Construction of Oxa-[n.2.1] Skeletons
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The first LA-catalyzed [3 + 2]IMCC of GDA-epoxides with carbon-carbon double bonds has been developed. This provides an efficient and general strategy for construction of bridged oxa-[n.2.1] skeletons. A novel SN-like mechanism through a carbon-carbon bond cleavage of epoxide ring has been proposed.
- Chen, Lu,Tian, Jun,Zhan, Yizhou,Ren, Jun,Wang, Zhong-Wen
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supporting information
p. 695 - 699
(2019/06/13)
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- Cobalt-Catalyzed N-O and C-C Bond Cleavage in 1,2-Oxazetidines: Solvent-Controlled C-H Aminomethylation and Hydroxymethylation of Heteroarenes
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An efficient cobalt-catalyzed ring-opening reaction of bench-stable 1,2-oxazetidines with heteroarenes was unprecedentedly developed. The sustainable Cp?Co(III) catalyst enables a distinctive merger of C-H activation with concomitant N-O and C-C cleavages of 1,2-oxazetidine, leading to site-selective C-H aminomethylation and hydroxymethylation of heteroaromatic compounds containing a broad range of functional groups. Preliminary control experiments unravel some essential mechanistic features of this one-pot transformation.
- Li, Song,Shi, Pengfei,Liu, Rui-Hua,Hu, Xu-Hong,Loh, Teck-Peng
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supporting information
p. 1602 - 1606
(2019/03/29)
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- On/Off O2 Switchable Photocatalytic Oxidative and Protodecarboxylation of Carboxylic Acids
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Photoredox catalysis in recent years has manifested a powerful branch of science in organic synthesis. Although merging photoredox and metal catalysts has been a widely used method, switchable heterogeneous photoredox catalysis has rarely been considered. Herein, we open a new window to use a switchable heterogeneous photoredox catalyst which could be turned on/off by changing a simple stimulus (O2) for two opponent reactions, namely, oxidative and protodecarboxylation. Using this strategy, we demonstrate that Au@ZnO core-shell nanoparticles could be used as a switchable photocatalyst which has good catalytic activity to absorb visible light due to the localized surface plasmon resonance effect of gold, can decarboxylate a wide range of aromatic and aliphatic carboxylic acids, have multiple reusability, and are a reasonable candidate for synthesizing both aldehydes/ketones and alkane/arenes in a large-scale set up. Some biologically active molecules are also shown via examples of the direct oxidative and protodecarboxylation which widely provided pharmaceutical agents.
- Bazyar, Zahra,Hosseini-Sarvari, Mona
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p. 13503 - 13515
(2019/10/11)
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- Lithiation of 1-alkoxyindole derivatives
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Lithiation of 1-alkoxyindoles, 3-dimethylaminomethyl- and 3-dimethylaminoethyl-1-methoxyindole occurred regioselectively at the 2-position. The introduction of a sterically bulky group into the 2-position of 3-dimethylaminomethyl-1-methoxyindoles directed the lithiation to the 4-position.
- Nakagawa, Kyoko,Kobayashi, Tetsuya,Kawasaki, Toshiya,Somei, Masanori
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p. 968 - 997
(2019/04/26)
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- Design, synthesis and biological evaluation of novel indole-benzimidazole hybrids targeting estrogen receptor alpha (ER-α)
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In the course of efforts to develop novel selective estrogen receptor modulators (SERMs), indole-benzimidazole hybrids were designed and synthesised by fusing the indole nucleus with benzimidazole. All the compounds were first inspected for anti-prolifera
- Singla, Ramit,Gupta, Kunj Bihari,Upadhyay, Shishir,Dhiman, Monisha,Jaitak, Vikas
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p. 206 - 219
(2018/02/10)
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- Temperature-modulated diastereoselective transformations of 2-vinylindoles to tetrahydrocarbazoles and tetrahydrocycloheptadiindoles
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Direct and expedient access to densely substituted tetrahydrocarbazoles and tetrahydrocycloheptadiindoles bearing multiple contiguous stereocentres has been achieved via a two-fold divergent diastereoselective (dr up to >99:1) transformation of 2-vinylindoles. The high-yielding conversions (yield up to 87%) that are amenable for a wide range of substituted 2-vinylindoles proceed through Lewis acid-catalyzed [4 + 2] and [4 + 3] cyclization-aromatization cascade reactions, respectively, involving a heretofore-unprecedented reversal of the polarity (umpolung) of 2-vinylindoles. The two synthetic routes are effortlessly transposable into each other by merely modulating the temperature to furnish the corresponding products in a selective and exclusive fashion. In addition, another novel synthetic route to tetrahydroindolocarbazoles has been developed that advances via a formal [4 + 2] cyclization of 4-vinylindoles involving sequential C3 Michael addition-dearomatization-aromatization cascade reactions.
- Wani, Imtiyaz Ahmad,Bhattacharyya, Aditya,Sayyad, Masthanvali,Ghorai, Manas K.
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p. 2910 - 2922
(2018/05/03)
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- Synthetic and Mechanistic Investigation of an Oxime Ether Electrocyclization Approach to Heteroaromatic Boronic Acid Derivatives
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A range of functionalized heteroaromatic boronic acid derivatives are readily accessed by a diboration/6π-electrocyclization sequence. This study revealed the surprising observation that there is a direct relationship between oxime ether stereochemistry and reactivity towards electrocyclization. Specifically, E-oxime ethers are found to be significantly more reactive than their Z-counterparts (stereochemistry relative to azatriene scaffold). In contrast, the configuration at the azatriene alkene terminus has little impact on reaction rates. Computational analysis offers a rationale for this observation; a Nlone pair→C=C π* orbital interaction lowers the energy of the transition state in the electrocyclization of E-oxime ethers. Finally, unreactive Z-oxime ethers can be converted to the corresponding heterocyclic products by a photolytically promoted E→Z isomerization and electrocyclization sequence.
- Mora-Radó, Helena,Sotorríos, Lia,Ball-Jones, Matthew P.,Bialy, Laurent,Czechtizky, Werngard,Méndez, María,Gómez-Bengoa, Enrique,Harrity, Joseph P. A.
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p. 9530 - 9534
(2018/07/14)
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- Divergence in Ynone Reactivity: Atypical Cyclization by 3,4-Difunctionalization versus Rare Bis(cyclization)
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Functionalized ynones can be activated by Tf2C=CH2, which was generated in situ, to form zwitterionic species. These species were trapped in an intramolecular fashion by several nucleophiles to generate two major types of triflones in a divergent manner. Through fine-tuning of the reaction temperature, bis(triflyl)-6-membered- or (triflyl)-5-membered-fused-heterocycles were achieved in reasonable yields in a totally selective manner. In this way, bis(triflyl)flavones, bis(triflyl)thioflavones, bis(triflyl)selenoflavones, (triflyl)benzothienopyrans, (triflyl)benzoselenophenopyrans, (triflyl)vinyl aurones, and (triflyl)pyranoindoles were constructed. Conceivable mechanistic pathways were suggested on the basis of the isolation of several intermediates and the results from control experiments.
- Alcaide, Benito,Almendros, Pedro,Lázaro-Milla, Carlos,Delgado-Martínez, Patricia
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supporting information
p. 8186 - 8194
(2018/06/15)
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- Palladium-Catalyzed Reductive Conversion of Acyl Fluorides via Ligand-Controlled Decarbonylation
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Ligand-controlled non-decarbonylative and decarbonylative conversions of acyl fluorides were developed using a Pd(OAc)2/Et3SiH combination. When tricyclohexylphosphine (PCy3) was used as the ligand, aldehydes were obtained as simple reductive conversion products. The use of 1,2-bis(dicyclohexylphosphino)ethane (Cy2P(CH2)2PCy2, DCPE) as the ligand, however, favored the formation of hydrocarbons, which are decarbonylative reduction products.
- Ogiwara, Yohei,Sakurai, Yuka,Hattori, Hiroyuki,Sakai, Norio
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supporting information
p. 4204 - 4208
(2018/07/29)
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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 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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supporting information
p. 14207 - 14212
(2018/09/14)
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- Synthesis and biological evaluation of potential inhibitors of the cysteine proteases cruzain and rhodesain designed by molecular simplification
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Analogues of 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]indol-4-amine 1, a known cruzain inhibitor, were synthesized using a molecular simplification strategy. Five series of analogues were obtained: indole, pyrimidine, quinoline, aniline and pyrrole derivatives. The activity of the compounds was evaluated against the enzymes cruzain and rhodesain as well as against Trypanosoma cruzi amastigote and trypomastigote forms. The 4-aminoquinoline derivatives showed promising activity against both enzymes, with IC50values ranging from 15 to 125?μM. These derivatives were selective inhibitors for the parasitic proteases, being unable to inhibit mammalian cathepsins B and S. The most active compound against cruzain (compound 5a; IC50?=?15?μM) is considerably more synthetically accessible than 1, while retaining its ligand efficiency. As observed for the original lead, compound 5a was shown to be a competitive enzyme inhibitor. In addition, it was also active against T. cruzi (IC50?=?67.7?μM). Interestingly, the pyrimidine derivative 4b, although inactive in enzymatic assays, was highly active against T. cruzi (IC50?=?3.1?μM) with remarkable selectivity index (SI?=?128) compared to uninfected fibroblasts. Both 5a and 4b exhibit drug-like physicochemical properties and are predicted to have a favorable ADME profile, therefore having great potential as candidates for lead optimization in the search for new drugs to treat Chagas disease.
- Braga, Saulo Fehelberg Pinto,Martins, Luan Carvalho,da Silva, Elany Barbosa,Sales Júnior, Policarpo Ademar,Murta, Silvane Maria Fonseca,Romanha, Alvaro José,Soh, Wai Tuck,Brandstetter, Hans,Ferreira, Rafaela Salgado,de Oliveira, Renata Barbosa
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p. 1889 - 1900
(2017/03/08)
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- Simple and Efficient Ruthenium-Catalyzed Oxidation of Primary Alcohols with Molecular Oxygen
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Oxidative transformations utilizing molecular oxygen (O2) as the stoichiometric oxidant are of paramount importance in organic synthesis from ecological and economical perspectives. Alcohol oxidation reactions that employ O2are scarce in homogeneous catalysis and the efficacy of such systems has been constrained by limited substrate scope (most involve secondary alcohol oxidation) or practical factors, such as the need for an excess of base or an additive. Catalytic systems employing O2as the “primary” oxidant, in the absence of any additive, are rare. A solution to this longstanding issue is offered by the development of an efficient ruthenium-catalyzed oxidation protocol, which enables smooth oxidation of a wide variety of primary, as well as secondary benzylic, allylic, heterocyclic, and aliphatic, alcohols with molecular oxygen as the primary oxidant and without any base or hydrogen- or electron-transfer agents. Most importantly, a high degree of selectivity during alcohol oxidation has been predicted for complex settings. Preliminary mechanistic studies including18O labeling established the in situ formation of an oxo–ruthenium intermediate as the active catalytic species in the cycle and involvement of a two-electron hydride transfer in the rate-limiting step.
- Ray, Ritwika,Chandra, Shubhadeep,Maiti, Debabrata,Lahiri, Goutam Kumar
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supporting information
p. 8814 - 8822
(2016/07/06)
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- Barbiturate compound, preparing method and application thereof
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The invention belongs to the field of medicinal chemistry, and discloses a barbiturate compound, a preparing method and application thereof. Specifically, the invention relates to the compound as shown in formula I, and a medicinal usage thereof as a selective LSD1 reversible inhibitor, particular to the application in preparing of antitumor medicine. A test shows that the compound in formula I can efficiently reversibly inhibit LSD1 activity, and has a weak inhibition action for homologous proteins MAO-A and MAO-B, can intensively induce differentiation of leukemia cell NB4 and obviously enhance the methylation level of primers H3K4me1 and H3K4me2 of the LSD1.
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Paragraph 0037; 0038; 0039; 0040
(2016/10/09)
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- Electronic Structure and Multicatalytic Features of Redox-Active Bis(arylimino)acenaphthene (BIAN)-Derived Ruthenium Complexes
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The article examines the newly designed and structurally characterized redox-active BIAN-derived [Ru(trpy)(R-BIAN)Cl]ClO4 ([1a]ClO4-[1c]ClO4), [Ru(trpy)(R-BIAN)(H2O)](ClO4)2 ([3a](ClO4)2-[3c](ClO4)2), and BIAO-derived [Ru(trpy)(BIAO)Cl]ClO4 ([2a]ClO4) (trpy = 2,2′:6′,2′′-terpyridine, R-BIAN = bis(arylimino)acenaphthene (R = H (1a+, 3a2+), 4-OMe (1b+, 3b2+), 4-NO2 (1c+, 3c2+), BIAO = [N-(phenyl)imino]acenapthenone). The experimental (X-ray, 1H NMR, spectroelectrochemistry, EPR) and DFT/TD-DFT calculations of 1an-1cn or 2an collectively establish {RuII-BIAN0} or {RuII-BIAO0} configuration in the native state, metal-based oxidation to {RuIII-BIAN0} or {RuIII-BIAO0}, and successive electron uptake processes by the α-diimine fragment, followed by trpy and naphthalene π-system of BIAN or BIAO, respectively. The impact of the electron-withdrawing NO2 function in the BIAN moiety in 1c+ has been reflected in the five nearby reduction steps within the accessible potential limit of -2 V versus SCE, leading to a fully reduced BIAN4- state in [1c]4-. The aqua derivatives ({RuII-OH2}, 3a2+-3c2+) undergo simultaneous 2e-/2H+ transfer to the corresponding {RuIV-O} state and the catalytic current associated with the RuIV/RuV response probably implies its involvement in the electrocatalytic water oxidation. The aqua derivatives (3a2+-3c2+) are efficient and selective precatalysts in transforming a wide variety of alkenes to corresponding epoxides in the presence of PhI(OAc)2 as an oxidant in CH2Cl2 at 298 K as well as oxidation of primary, secondary, and heterocyclic alcohols with a large substrate scope with H2O2 as the stoichiometric oxidant in CH3CN at 343 K. The involvement of the {RuIV-O} intermediate as the active catalyst in both the oxidation processes has been ascertained via a sequence of experimental evidence.
- Singha Hazari, Arijit,Ray, Ritwika,Hoque, Md Asmaul,Lahiri, Goutam Kumar
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p. 8160 - 8173
(2016/08/24)
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- AZA-HETEROARYL COMPOUNDS AS PI3K-GAMMA INHIBITORS
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The present invention provides aza-heteroaryl derivatives of Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, Z, A, W, R4, R5, and R6 are defined herein, that inhibit the activity of phosphoinositide 3-kinases-gamma (PI3Kγ) and are useful in the treatment of diseases related to the activity of PI3Kγ including, for example, autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases.
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Paragraph 0363
(2016/09/12)
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- PAIN RELIEF COMPOUNDS
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The present invention relates to the use of compounds for the treatment or prevention of pain in mammals, in particularly in human beings, and also to a process for preparing these compounds.
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- One-Pot Base-Mediated Synthesis of Functionalized Aza-Fused Polycyclic Quinoline Derivatives
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A new one-pot protocol has been developed for the facile and efficient synthesis of aza-fused polycyclic quinolines (e.g., pyrrolo[1,2-a]quinolines) by the base-catalyzed reaction of 2-formylpyrroles and 2-halophenylacetonitriles. This reaction proceeded under transition metal-free conditions and showed high functional group tolerance, with the desired products being formed in good yields.
- Jiang, Zeng-Qiang,Miao, Da-Zhuang,Tong, Yao,Pan, Qiang,Li, Xiao-Tong,Hu, Ren-He,Han, Shi-Qing
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p. 1913 - 1921
(2015/06/30)
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- Construction of Benzo[c]carbazoles and Their Antitumor Derivatives through the Diels-Alder Reaction of 2-Alkenylindoles and Arynes
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The direct assembly of benzo[c]carbazole derivatives via the Diels-Alder reaction of arynes and easily accessible 2-alkenylidoles was reported. By employing different aryne precursor loads, 6,7-dihydrobenzo[c]carbazoles or aryl-substituted 7,11b-dihydrobenzo[c]carbazoles could be controllably generated in good to excellent yields under a nitrogen atmosphere. On the other hand, when the reaction was conducted under oxygen, oxidated/aromatized product benzo[c]carbazoles could be generated directly with high selectivity and efficiency in a one-step manner. Interestingly, the benzo[c]carbazole-5-carboxamide amidation derivatives of the above products showed good antitumor activities. The inhibitory effect of these molecules against cancer cells was also described.
- Sha, Feng,Tao, Yuan,Tang, Chen-Yu,Zhang, Fei,Wu, Xin-Yan
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p. 8122 - 8133
(2015/09/01)
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- Facile Synthesis of Carbazoles via a Tandem Iodocyclization with 1,2-Alkyl Migration and Aromatization
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A strategy for the synthesis of iodocarbazoles through a tandem iodocyclization with migration and aromatization is presented. This sequential cascade process is concisely conducted at room temperature and in a short time. Moreover, the obtained halides c
- Wang, Jia,Zhu, Hai-Tao,Qiu, Yi-Feng,Niu, Yuan,Chen, Si,Li, Ying-Xiu,Liu, Xue-Yuan,Liang, Yong-Min
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supporting information
p. 3186 - 3189
(2015/06/30)
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- Rhodium(III)-catalyzed cyclative capture approach to diverse 1-aminoindoline derivatives at room temperature
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A RhIII-catalyzed C-H activation/cyclative capture approach, involving a nucleophilic addition of C(sp3)-Rh species to polarized double bonds is reported. This constitutes the first intermolecular catalytic method to directly access 1-aminoindolines with a broad substituent scope under mild conditions.
- Zhao, Dongbing,Vsquez-Cspedes, Suhelen,Glorius, Frank
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p. 1657 - 1661
(2015/01/30)
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- Inhibition of 5-oxo-6,8,11,14-eicosatetraenoic acid-induced activation of neutrophils and eosinophils by novel indole oxe receptor antagonists
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5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a 5-lipoxygenase product that is a potent granulocyte chemoattractant, which induces the infiltration of eosinophils into human skin when injected intradermally. It could therefore be an important proinflammatory mediator in eosinophilic diseases such as asthma and allergic rhinitis, and the OXE receptor, which mediates its actions, is therefore an attractive drug target. Using a structure-based approach in which substituents mimicking the essential polar (C1-C5) and hydrophobic (C15-C20) regions of 5-oxo-ETE were incorporated on an indole scaffold, we identified two potent selective OXE antagonists with IC50 values of about 30 nM. Neither compound displayed agonist activity and both inhibited 5-oxo-ETE-induced chemotaxis and actin polymerization and were relatively resistant to metabolism by rat liver homogenates. The active enantiomers of these racemic antagonists were even more potent, with IC50 values of 10 nM. These selective OXE antagonists could potentially be useful therapeutic agents in allergic diseases such as asthma.
- Gore, Vivek,Gravel, Sylvie,Cossette, Chantal,Patel, Pranav,Chourey, Shishir,Ye, Qiuji,Rokach, Joshua,Powell, William S.
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p. 364 - 377
(2014/02/14)
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- Gold-catalyzed oxidative rearrangement involving 1,2-acyl migration: Efficient synthesis of functionalized dihydro-γ-carbolines from α-(2-indolyl) propargylic alcohols and imines
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Smooth moves with a nifty side step: A gold-catalyzed transformation of α-(2-indolyl) propargylic alcohols with imines in the presence of the oxidant 8-isopropylquinoline N-oxide provided rapid access to highly functionalized dihydro-γ-carbolines (see scheme). The reaction mechanism is proposed to involve intermolecular trapping of an α-carbonyl gold carbenoid intermediate, followed by cyclization and a novel gold-assisted 1,2-acyl migration.
- Wang, Lu,Xie, Xin,Liu, Yuanhong
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p. 13302 - 13306
(2014/01/06)
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- HETEROCYCLIC COMPOUNDS AND METHODS FOR THEIR USE
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The present invention relates to heterocyclic compounds useful for antagonising angiotensin II Type 2 (AT2) receptor. More particularly the invention relates to piperidine compounds, compositions containing them and their use in methods of treating or preventing disorders or diseases associated with AT2 receptor function including neuropathic pain, inflammatory pain, conditions associated with neuronal hypersensitivity, impaired nerve conduction velocity, cell proliferation disorders, disorders associated with an imbalance between bone resorption and bone formation and disorders associated with aberrant nerve regeneration.
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Page/Page column 52
(2013/08/15)
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- SERINE/THREONINE KINASE INHIBITORS
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Compounds of Formula I or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof are provided, which are useful for the treatment of hyperproliferative, pain and inflammatory diseases. Methods of using compounds of Formula I or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.
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Paragraph 00423
(2013/09/12)
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- 5-Oxo-ETE receptor antagonists
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5-Oxo-ETE is the most powerful eosinophil chemoattractant among lipid mediators. Eosinophil infiltration into the lungs of asthmatics may be responsible for the late phase of inflammatory asthma. We have designed and synthesized a 5-oxo-ETE receptor antagonist, the purpose of which is to prevent eosinophil migration to the lung during an asthma attack and thereby reduce asthma symptoms.
- Gore, Vivek,Patel, Pranav,Chang, Chih-Tsung,Sivendran, Sashikala,Kang, Namin,Ouedraogo, Yannick P.,Gravel, Sylvie,Powell, William S.,Rokach, Joshua
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p. 3725 - 3732
(2013/06/27)
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- Conformational, steric and electronic effects on the site- and chemoselectivity of the metal-catalyzed reaction of N-bis(trimethylsilyl)methyl, N-(2-indolyl)methyl α-diazoamides
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The Rh(ii)- and Cu(ii)-catalyzed reactions of N-bis(trimethylsilyl)methyl, N-(2-indolyl)methyl α-diazoamides are investigated to delineate how conformational, steric and electronic factors influence the site- and chemoselectivity of the metallocarbenoid r
- Zhang, Bao,Wee, Andrew G. H.
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supporting information; experimental part
p. 4597 - 4608
(2012/07/28)
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- A novel intramolecular Ugi 3CC for the synthesis of N-alkyl-3-oxo-2-aryl-1, 2,3,4-tetrahydropyrazino[1,2-a]indole-1-carboxamides
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An intramolecular Ugi reaction of 2-(2-formyl-1H-indol-1-yl)acetic acid with aryl amines and isocyanides has been developed to produce a novel class of N-alkyl-3-oxo-2-aryl-1,2,3,4-tetrahydropyrazino[1,2-a]indole-1-carboxamides in good yields. This is the
- Subba Reddy,Dey, Sujit Kumar,Yadav,Sridhar
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p. 3676 - 3679
(2012/09/21)
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- Aminooxazole Inhibitors of Cyclin Dependent Kinases
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Oxazole derivatives are described. The inventive compounds are useful as kinase inhibitors, and may be used in the treatment of cancer, such as prostate cancer, lung cancer, breast cancer, colon cancer, leukemia, CNS cancer, melanoma, ovarian cancer, and
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- Studies toward the synthesis of (R)-(+)-harmicine
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The study toward the total synthesis of (R)-(+)-harmicine is reported in this paper. The enantioselective synthesis of pyrrolidinone, the main backbone of of (R)-(+)-harmicine, has been completed by the methodology based on photo-induced Wolff rearrangement of α-diazo-β-carbonyl compounds. Copyright
- Mo, Fanyang,Li, Fei,Qiu, Di,Zhang, Yan,Wang, Jianbo
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p. 2297 - 2302,6
(2020/09/16)
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- Optimization and structure-activity relationships of a series of potent inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase as novel antimicrobial agents
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A novel series of hydrazones were synthesized and evaluated as inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK). PK has been identified as one of the most highly connected 'hub proteins' in MRSA. PK has been shown to b
- Kumar, Nag S.,Amandoron, Emily A.,Cherkasov, Artem,Brett Finlay,Gong, Huansheng,Jackson, Linda,Kaur, Sukhbir,Lian, Tian,Moreau, Anne,Labrière, Christophe,Reiner, Neil E.,See, Raymond H.,Strynadka, Natalie C.,Thorson, Lisa,Wong, Edwin W.Y.,Worrall, Liam,Zoraghi, Roya,Young, Robert N.
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supporting information
p. 7069 - 7082
(2013/01/15)
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- One-step synthesis of 2-amino-5h-pyrimido[5,4-b]indoles, substituted 2-(1,3,5-triazin-2-yl)-1h-indoles, and 1,3,5-triazines from aldehydes
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An efficient one-step synthesis of 2-amino-5H-pyrimido[5,4-b]indoles through a copper-catalyzed cascade reaction between 3-haloindole-2-carbaldehydes and guanidine hydrochloride is described. In contrast, the base-mediated reactions of either 3-haloindole-2-carbaldehydes or substituted indole-2-carbaldehydes with substituted amidine hydrochlorides in DMSO result in the formation of 2-(1,3,5-triazin-2-yl)-1H-indole derivatives in one step in excellent yields. Studies toward exploring the utility of the method demonstrate that even substituted benzaldehydes undergo a similar reaction to efficiently yield 2,4,6-trisubstituted 1,3,5-triazines. A plausible mechanism for the formation of substituted 1,3,5-triazines identifies the role of DMSO as an oxidant during the reaction. The synthesis of 2-amino-5H-pyrimido[5,4-b]indoles from 3-haloindole-2-carbaldehyde and guanidine hydrochloride is described. In contrast, 3-haloindole-2-carbaldehydes or indole-2-carbaldehydes react with substituted amidine hydrochlorides to give 2-(1,3,5-triazin-2-yl)-1H-indole derivatives in excellent yields. The latter protocol was used to prepare 2,4,6-trisubstituted 1,3,5-triazines.
- Biswas, Subhasish,Batra, Sanjay
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scheme or table
p. 3492 - 3499
(2012/08/13)
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- ANTI-BACTERIAL PYRUVATE KINASE MODULATOR COMPOUNDS, COMPOSITIONS, USES, AND METHODS
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Compounds having a structure of Formulas A-C are provided. Uses of such compounds as an antibiotic, including both gram-negative and gram-positive micro-organisms, as well as methods of treatment and uses involving such compounds are provided.
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Page/Page column 48; 84
(2012/05/05)
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- New indole amide derivatives as potent CRTH2 receptor antagonists
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A new series of indole amide acting as hCRTH2 receptor ligands had been explored and are described herein. Several amide derivatives displaying low nanomolar activity in hCRTH2 binding and whole blood assays were identified. They were found to behave as a full antagonists, exhibiting good selectivity over related prostaglandin receptors. Also, prototypical compounds in this novel series which displayed acceptable CYP profiles and were orally bioavailable in rats were identified.
- Zaghdane, Helmi,Boyd, Michael,Colucci, John,Simard, Daniel,Berthelette, Carl,Leblanc, Yves,Wang, Zhaoyin,Houle, Robert,Lévesque, Jean Fran?ois,Molinaro, Carmela,Hamel, Martine,Stocco, Rino,Sawyer, Nicole,Sillaots, Susan,Gervais, Fran?ois,Gallant, Michel
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p. 3471 - 3474
(2011/07/07)
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- Synthesis of 2-and 3-indolylpyrroles via 1,3-dipolar cycloadditions of muenchnones and nitroalkenes
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A series of 2-and 3-indolylpyrroles were generated via 1,3-dipolar cycloadditions between (2-nitrovinyl)indoles and symmetrical and unsymmetrical 1,3-oxazolium-5-olates (muenchnones). The Japan Institute of Heterocyclic Chemistry.
- Lopchuk, Justin M.,Gribble, Gordon W.
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scheme or table
p. 1617 - 1631
(2011/05/04)
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- Ionic diamine rhodium complex catalyzed reductive N-heterocyclization of 2-nitrovinylarenes
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Ionic diamine rhodium complex (1) catalyzes the reductive N-cyclization of 2-vinylnitroarenes using carbon monoxide as a reducing agent to afford functionalized indoles. The catalytic system allows direct access to indoles with ester and ketone groups at the 2- or 3-position, in good yields.
- Okuro, Kazumi,Gurnham, Joanna,Alper, Howard
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supporting information; experimental part
p. 4715 - 4720
(2011/07/08)
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