- Design, synthesis and biological activity of selective hCAs inhibitors based on 2-(benzylsulfinyl)benzoic acid scaffold
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A large library of derivatives based on the scaffold of 2-(benzylsulfinyl)benzoic acid were synthesised and tested as atypical inhibitors against four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). The exploration of the chemical space around the main functional groups led to the discovery of selective hCA IX inhibitors in the micromolar/nanomolar range, thus establishing robust structure-activity relationships within this versatile scaffold. HPLC separation of some selected chiral compounds and biological evaluation of the corresponding enantiomers was performed along with molecular modelling studies on the most active derivatives.
- Rotondi, Giulia,Guglielmi, Paolo,Carradori, Simone,Secci, Daniela,De Monte, Celeste,De Filippis, Barbara,Maccallini, Cristina,Amoroso, Rosa,Cirilli, Roberto,Akdemir, Atilla,Angeli, Andrea,Supuran, Claudiu T.
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p. 1400 - 1413
(2019/08/26)
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- Chemoselectivity for Alkene Cleavage by Palladium-Catalyzed Intramolecular Diazo Group Transfer from Azide to Alkene
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Alkenes can be cleaved by means of the (3+2) cycloaddition and subsequent cycloreversion of 1,3-dipoles, classically ozone (O3), but the azide (R?N3) variant is rare. Chemoselectivity for these azide to alkene diazo group transfers (DGT) is typically disfavored, thus limiting their synthetic utility. Herein, this work discloses a palladium-catalyzed intramolecular azide to alkene DGT, which grants chemoselectivity over competing aziridination. The data support a catalytic cycloreversion mechanism distinct from other known metal-catalyzed azide/alkene reactions: nitrenoid/metalloradical and (3+2) cycloadditions. Kinetics experiments reveal an unusual mechanistic profile in which the catalyst is not operative during the rate-controlling step, rather, it is active during the product-determining step. Catalytic DGT was used to synthesize N-heterocyclic quinazolinones, a medicinally relevant structural core. We also report on the competing aziridination and subsequent ring expansion to another N-heterocyclic core structure of interest, benzodiazepinones.
- Frost, Grant B.,Mittelstaedt, Michaela N.,Douglas, Christopher J.
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p. 1727 - 1732
(2019/01/09)
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- Para-Selective C-H Olefination of Aniline Derivatives via Pd/S,O-Ligand Catalysis
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Herein we report a highly para-selective C-H olefination of aniline derivatives by a Pd/S,O-ligand-based catalyst. The reaction proceeds under mild reaction conditions with high efficiency and broad substrate scope, including mono-, di-, and trisubstituted tertiary, secondary, and primary anilines. The S,O-ligand is responsible for the dramatic improvements in substrate scope and the high para-selectivity observed. This methodology is operationally simple, scalable, and can be performed under aerobic conditions.
- Naksomboon, Kananat,Poater, Jordi,Bickelhaupt, F. Matthias,Fernández-Ibá?ez, M. ángeles
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supporting information
p. 6719 - 6725
(2019/05/06)
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- Rapid and reversible hydrazone bioconjugation in cells without the use of extraneous catalysts
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The amenability of hydrazone linkages to disassemble via either hydrolysis in mildly acidic aqueous solutions or transimination upon treatment with amine nucleophiles renders them extremely attractive for applications in chemical biology, drug delivery and materials science. Unfortunately, however, the use of hydrazones is hampered by the extremely slow intrinsic rates of their formation from their hydrazine and carbonyl precursors. Consequently, hydrazone formation is typically performed in the presence of a large excess of cytotoxic aniline-based nucleophilic catalysts, rendering hydrazones unsuitable for biological applications that entail their formation in cells. Herein, we report a hydrazine scaffold - o-amino benzyl hydrazine - that rapidly forms hydrazones via intramolecular nucleophilic catalysis, thereby obviating the use of extraneous catalysts. We demonstrate the use of this scaffold for rapid and reversible peptide and protein hydrazone bioconjugation and also for reversible fluorescent labeling of sialylated glycoproteins and choline lipids in mammalian cells.
- Nisal, Rahul,Jose, Gregor,Shanbhag, Chitra,Kalia, Jeet
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p. 4304 - 4310
(2018/06/22)
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- Electrocatalytic C-H/N-H Coupling of 2′-Aminoacetophenones for the Synthesis of Isatins
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2′-Aminoacetophenones undergo a C(sp3)-H oxidation followed by intramolecular C-N bond formation by virtue of a simple electrochemical oxidation in the presence of n-Bu4NI, providing various isatins with moderate to good yields. The reaction intermediates were detected, and a radical-based pathway was proposed.
- Qian, Peng,Su, Ji-Hu,Wang, Yukang,Bi, Meixiang,Zha, Zhenggen,Wang, Zhiyong
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p. 6434 - 6440
(2017/06/23)
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- Investigation into the stability and reactivity of the pentacyclic alkaloid dehydroevodiamine and the benz-analog thereof
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Limited synthetic approaches to obtain the biologically active alkaloid dehydroevodiamine (DHED) are known to date. Undesired demethylation in the most widely applied route was found to be a hampering side reaction for the benz-DHED derivative leading to a quinazolinone, which represents a benz-rutaecarpine derivative. For rutaecarpine, a related plant alkaloid, many different synthetic approaches have been described. Alternative reaction procedures to obtain DHED such as methylation of rutaecarpine and oxidation of evodiamine were investigated to make DHED more easily accessible and the latter method proved to be the most successful one. Furthermore, the remarkable equilibrium between the ring closed quinazolinium and the ring open form of the compounds was systematically investigated by UV-vis measurements. The ring open form and the quinazolinium salt, form the same species when incubated in buffer solution for 24 h. A better soluble form, i.e., 'hydroxyevodiamine', seems to represent the biologically active form that has not yet been described.
- Wehle, Sarah,Espargaró, Alba,Sabaté, Raimon,Decker, Michael
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p. 2535 - 2543
(2016/04/26)
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- A General and Direct Reductive Amination of Aldehydes and Ketones with Electron-Deficient Anilines
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In our ongoing efforts in preparing tool compounds for investigating and controlling the biosynthesis of phenazines, we recognized the limitations of existing protocols for C-N bond formation of electron-deficient anilines when using reductive amination. After extensive optimization, we have established three robust and scalable protocols for the reductive amination of ketones with electron-deficient anilines, by using either BH3·THF/AcOH/CH2Cl2 (method A), with reaction times of several hours, or the more powerful combinations BH3·THF/TMSCl/DMF (method B) and NaBH4/TMSCl/DMF (method C), which give full conversions for most substrates within 10 to 25 minutes. The scope and limitations of these reactions have been defined for 12 anilines and 14 ketones.
- Pletz, Jakob,Berg, Bernhard,Breinbauer, Rolf
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supporting information
p. 1301 - 1317
(2016/05/02)
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- Sunlight-Driven Forging of Amide/Ester Bonds from Three Independent Components: An Approach to Carbamates
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A photoredox catalytic route to carbamates enabled by visible irradiation (or simply sunlight) has been developed. This process leads to a novel approach to the construction of heterocyclic rings wherein the amide or ester motifs of carbamates were assembled from three isolated components. Large-scale experiments were realized by employing continuous flow techniques, and reuse of photocatalyst demonstrated the green and sustainable aspects of this method.
- Zhao, Yating,Huang, Binbin,Yang, Chao,Chen, Qingqing,Xia, Wujiong
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supporting information
p. 5572 - 5575
(2016/11/17)
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- Reinvestigating Raney nickel mediated selective alkylation of amines with alcohols via hydrogen autotransfer methodology
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An efficient, cost-effective use of Raney nickel (R-Ni) a widely used industrial catalyst for N-alkylation using alcohols is highlighted here. The work describes the scope and capability of R-Ni in hydrogen autotransfer reactions enabling its widespread use in the Chemical and Pharmaceutical industry. R-Ni of W4, T4, and W7 grades were prepared and evaluated for alkylation of amines. The best activity and selectivity for mono alkylation of amines were obtained using W4 R-Ni at 1:4 moles of amine to alcohol in xylene at reflux. T4 R-Ni also showed ability to form stable imines. The prepared R-Ni was also recycled and reused for N-alkylation reaction. The optimized methodology was applied for synthesis of Active Pharmaceutical ingredients Piribedil and Mepyramine. The simplicity and wide substrate scope makes this method a preferred Hydrogen Auto-transfer protocol for the alkylation of amines.
- Mehta, Astha,Thaker,Londhe,Nandan, Santosh R.
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p. 241 - 251
(2014/05/20)
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- Synthesis and anti-parasitic activity of a novel quinolinone-chalcone series
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A series of novel quinolinone-chalcone hybrids and analogues were designed, synthesized and their biological activity against the mammalian stages of Trypanosoma brucei and Leishmania infantum evaluated. Promising molecular scaffolds with significant microbicidal activity and low cytotoxicity were identified. Quinolinone-chalcone 10 exhibited anti-parasitic properties against both organisms, being the most potent anti-L. infantum agent of the entire series (IC50 value of 1.3 ± 0.1 μM). Compounds 4 and 11 showed potency toward the intracellular, amastigote stage of L. infantum (IC50 values of 2.1 ± 0.6 and 3.1 ± 1.05 μM, respectively). Promising trypanocidal compounds include 5 and 10 (IC 50 values of 2.6 ± 0.1 and 3.3 ± 0.1 μM, respectively) as well as 6 and 9 (both having IC50 values of 5 μM). Chemical modifications on the quinolinone-chalcone scaffold were performed on selected compounds in order to investigate the influence of these structural features on antiparasitic activity.
- Roussaki, Marina,Hall, Belinda,Lima, Sofia Costa,Da Silva, Anabela Cordeiro,Wilkinson, Shane,Detsi, Anastasia
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supporting information
p. 6436 - 6441
(2013/11/19)
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- Benzhydrylquinazolinediones: Novel cytosolic phospholipase A2α inhibitors with improved physicochemical properties
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The synthesis and optimization of a class of trisubstituted quinazoline-2,4(1H,3H)-dione cPLA2α inhibitors are described. Utilizing pharmacophores that were found to be important in our indole series, we discovered inhibitors with reduced lipophilicity and improved aqueous solubility. These compounds are active in whole blood assays, and cell-based assay results indicate that prevention of arachidonic acid release arises from selective cPLA2α inhibition.
- Kirincich, Steven J.,Xiang, Jason,Green, Neal,Tam, Steve,Yang, Hui Y.,Shim, Jaechul,Shen, Marina W.H.,Clark, James D.,McKew, John C.
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experimental part
p. 4383 - 4405
(2009/10/23)
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- Highly reactive, general and long-lived catalysts for palladium-catalyzed amination of heteroaryl and aryl chlorides, bromides, and iodides: Scope and structure-activity relationships
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We describe a systematic study of the scope and relationship between ligand structure and activity for a highly efficient and selective class of catalysts containing sterically hindered chelating alkylphosphines for the amination of heteroaryl and aryl chlorides, bromides, and iodides. In the presence of this catalyst, aryl and heteroaryl chlorides, bromides, and iodides react with many primary amines in high yields with part-per-million quantities of palladium precursor and ligand. Many reactions of primary amines with both heteroaryl and aryl chlorides, bromides, and iodides occur to completion with 0.0005-0.05 mol % catalyst. A comparison of the reactivity of this catalyst for the coupling of primary amines at these loadings is made with catalysts generated from hindered monophosphines and carbenes, and these data illustrate the benefits of chelation. Studies on structural variants of the most active catalyst indicate that a rigid backbone in the bidentate structure, strong electron donation, and severe hindrance all contribute to its high reactivity. Thus, these complexes constitute a fourth-generation catalyst for the amination of aryl halides, whose activity complements catalysts based on monophosphines and carbenes.
- Shen, Qilong,Ogata, Tokutaro,Hartwig, John F.
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p. 6586 - 6596
(2008/12/22)
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- A practical method for preparation of 4-hydroxyquinolinone esters
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(Chemical Equation Presented) 4-Hydroxyquinolinone esters are a common motif for many medicinal agents. Several methods exist for preparation of these compounds, generally involving the use of sodium hydride, which raises significant safety issues and limits their application to large-scale synthesis. In this note a practical, safe, and general method that employs a combination of diisopropylethylamine and sodium tert-butoxide is described. This allows for the synthesis of 4-hydroxyquinolinone esters and amides in good yields.
- Beutner, Gregory L.,Kuethe, Jeffrey T.,Yasuda, Nobuyoshi
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p. 7058 - 7061
(2008/02/11)
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- Novel solid-phase synthetic method for combinatorial generation of a 4-hydroxyquinolin-2(1H)-one-based library
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Utilizing polymer-bound anthranilic acid derivatives, we were able to obtain 4-hydroxyquinolin-2(1H)-ones in 50-99% five-or six-step overall yields and 65-95% purities through the adaptation of a Dieckmann-type condensation reaction to a C-C bond-forming
- Jeon, Moon-Kook,Hyun, Ju La,Ha, Deok-Chan,Gong, Young-Dae
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p. 1431 - 1435
(2008/03/11)
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- An Investigation of the Reaction of 2-Aminobenzaldehyde Derivatives with Conjugated Nitro-olefins: An Easy and Efficient Synthesis of 3-Nitro-1,2-dihydroquinolines and 3-Nitroquinolines
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2-Aryl-3-nitro-1,2-dihydroquinolines 3 were prepared from the reaction of β-nitrostyrenes 2 and 2-aminobenzaldehyde 1 in the presence of DABCO. Not only β-nitrostyrenes but other alkyl nitro olefins also can be used in this reaction as well. When DDQ or silica gel was added to a solution of 3-nitro-1,2-dihydroquinolines 3, 3-nitro-2-substituted-quinolines 4 were obtained. When 2-aminobenzaldehyde derivatives 7 and 12 were reacted with β-nitrostyrenes 2, unique rearrangement products were produced.
- Yan, Ming-Chung,Tu, Zhijay,Lin, Chunchi,Ko, Shengkai,Hsu, Jianming,Yao, Ching-Fa
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p. 1565 - 1570
(2007/10/03)
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- Solution-phase combinatorial synthesis of 4-hydroxyquinolin-2(1H)-ones
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Ion-exchange resins catalyse an intramolecular Claisen-type condensation leading to the title compounds, and also serve to purify the products.
- Kulkarni, Bheemashankar A.,Ganesan
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p. 785 - 786
(2007/10/03)
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