- Thioester-appended organosilatranes: Synthetic investigations and application in the modification of magnetic silica surfaces
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The present investigation discloses a series of new organosilicon derivatives (3a-k) tailored with substituted benzoic acid modules (1a-k) via thioesterification with 3-mercaptopropylsilatrane (MPS). Product formation was authenticated using elemental analyses and different spectroscopic methods comprising FT-IR, NMR [1H, 13C] and LC-MS (Q-TOF). Thereafter, complete structural elucidation of compounds 3c and 3f was achieved by the single crystal X-ray technique. Photo-electronic inspection of all compounds by UV-Vis spectroscopy revealed their sensitivity towards substitution patterns. In addition, this is the first time that the potential of a silatranyl moiety has been tested for the modification of a silica surface pre-decorated with a magnetite core. The synthesis was achieved through a facile methodology involving chemical bonding at each stage, which proceeded without any external surfactant or template. The course of the reaction was followed by FT-IR, UV-Vis, XRD, TEM, FESEM, EDX and TGA techniques. Furthermore, the hybrid nanomaterial possessed significant sensorial ability toward copper ions, which makes the present protocol favourable for the construction of a new class of chelating ligands with an in-built multifunctional nanodevice.
- Singh, Gurjaspreet,Rani, Sunita,Arora, Aanchal,Aulakh, Darpandeep,Wriedt, Mario
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- Amide-tethered organosilatranes: Syntheses, structural characterization and photophysical properties
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A series of trimethoxysilanes and silatranes coupled with distinct aromatic moieties (biphenyl, thiophene, pyrazine and pyridine) through amide linkage are reported. The synthetic approach involved the amidation of 3-aminopropyltrimethoxysilane (APTMS) with various carboxylic acids via acid chlorides (1a-1g) to generate amidopropylsilanes (2a-2g). Transesterification of the resultant silanes with triethanolamine and tris(isopropanolamine) yielded unsubstituted (3a-3g) and 3,7,10-trimethylsubstitued organosilatranes (4a-4g), respectively. The compounds were successfully characterized by various spectroscopic techniques [IR, NMR (1H, 13C) and Mass] and elemental analysis. The complete structure elucidation for compounds 3a, 3c·H2O and 3f was carried out using single crystal X-ray diffraction analysis. The photophysical response was studied by UV-Vis absorption and fluorescence spectroscopy. These organosilatranes possess metal ion binding sites and can be put forth for advanced analytical applications.
- Singh, Gurjaspreet,Rani, Sunita,Saroa, Amandeep,Promila,Arora, Aanchal,Choquesillo-Lazarte, Duane
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- Regulation of a cerium(iv)-driven O2 evolution reaction using composites of liposome and lipophilic ruthenium complexes
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A composite containing a liposome and a lipophilic ruthenium complex was synthesized to regulate an O2 evolution reaction using cerium(iv) ammonium nitrate as an oxidizing reagent. We found that the surrounding environment of the reaction centre is an important factor for controlling the O2 evolution catalytic reaction. We successfully regulated the reaction activity using the linker length of the lipophilic ligand and using the head groups of the phospholipid component.
- Koshiyama, Tomomi,Kanda, Nao,Iwata, Koki,Honjo, Masayuki,Asada, Sana,Hatae, Tatsuru,Tsuji, Yasuhiro,Yoshida, Masaki,Okamura, Masaya,Kuga, Reiko,Masaoka, Shigeyuki,Ohba, Masaaki
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- Design and synthesis of N-benzoyl amino acid derivatives as DNA methylation inhibitors
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The inhibition of human DNA Methyl Transferases (DNMT) is a novel promising approach to address the epigenetic dysregulation of gene expression in different diseases. Inspired by the validated virtual screening hit NSC137546, a series of N-benzoyl amino acid analogues was synthesized and obtained compounds were assessed for their ability to inhibit DNMT-dependent DNA methylation in vitro. The biological screening allowed the definition of a set of preliminary structure–activity relationships and the identification of compounds promising for further development. Among the synthesized compounds, L-glutamic acid derivatives 22, 23, and 24 showed the highest ability to prevent DNA methylation in a total cell lysate. Compound 22 inhibited DNMT1 and DNMT3A activity in a concentration-dependent manner in the micromolar range. In addition, compound 22 proved to be stable in human serum and it was thus selected as a starting point for further biological studies.
- Garella, Davide,Atlante, Sandra,Borretto, Emily,Cocco, Mattia,Giorgis, Marta,Costale, Annalisa,Stevanato, Livio,Miglio, Gianluca,Cencioni, Chiara,Fernández-de Gortari, Eli,Medina-Franco, José L.,Spallotta, Francesco,Gaetano, Carlo,Bertinaria, Massimo
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- Purposeful regioselectivity control of the Birch reductive alkylation of biphenyl-4-carbonitrile
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Birch's reductive alkylation of biphenyl-4-carbonitrile (1) provides alkylated 1,4-dihydroderivatives of various structural types: 4-alkyl-4-phenylcyclohexa-2,5-dienone, 1,4-dialkyl-4-phenylcyclohexa-2,5-dienecarbonitrile (with the same or different alkyl fragments), and 4-(1-alkylcyclohexa-2,5-dienyl)benzonitrile. Each of these products become dominant depending on the nature of long-living anionic form generated from 1, namely, the stable product of two-electrons reduction – dianion (12?); 1-alkyl-4-cyano-1-phenylcyclohexa-2,5-dien-4-yl anion (1-Alk1–), originated due to the alkylation of dianion 12? at the position 1 of biphenyl moiety; or 1-(4-cyanophenyl)cyclohexa-2,5-dien-1-yl anion (1-H4’–), being the product of dianion 12? protonation at position 4′ by protonating reagent (MeOH or NH4Cl). The orientation of alkyl fragment incorporation into biphenyl-4-carbonitrile scaffold is in agreement with calculated electronic structure of the anionic species under investigation. The dominating type of their reactivity towards alkyl halides proved to be nucleophilic (SN2 mechanism).
- Fedyushin, Pavel A.,Peshkov, Roman Yu.,Panteleeva, Elena V.,Tretyakov, Evgeny V.,Beregovaya, Irina V.,Gatilov, Yuri V.,Shteingarts, Vitalij D.
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- An expedient ‘click’ approach for the synthetic evaluation of ester-triazole-tethered organosilica conjugates
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The present work articulates the synthesis of a new series of organo-functionalized triethoxysilanes derived from versatile carboxylic acids and 3-azidopropyltriethoxysilane in excellent yields. A proficient and convenient route implicating the Cu(I)-catalysed 1,3-cycloaddition of organic azide with terminal alkynes, labelled as click silylation, has been developed for the generation of ester-triazole-linked alkoxysilanyl scaffolds (4a–f). All the synthesized compounds have been thoroughly characterized using elemental analysis and Fourier transform infrared, 1H NMR and 13C NMR spectroscopic techniques. Importantly, the fabricated alkoxysilanes are potentially amenable for an in situ sol–gel condensation reaction with silica nanospheres leading to the incorporation of organic functionality via covalent grafting onto the nanostructured particle system. As a proof of concept, a one-pot preparation of organic–inorganic hybrid nanoparticles is presented using bis-silane 4?f. The efficiency and selectivity of the prepared nanocomposite towards metal ions is highlighted using adsorption experiments, and the immobilized nanoparticles present a high sensing efficiency towards Cu2+ and Pb2+ ions while demonstrating better response than that of the bulk material.
- Singh, Gurjaspreet,Rani, Sunita
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- Remarkably Efficient Iridium Catalysts for Directed C(sp2)-H and C(sp3)-H Borylation of Diverse Classes of Substrates
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Here we describe the discovery of a new class of C-H borylation catalysts and their use for regioselective C-H borylation of aromatic, heteroaromatic, and aliphatic systems. The new catalysts have Ir-C(thienyl) or Ir-C(furyl) anionic ligands instead of the diamine-type neutral chelating ligands used in the standard C-H borylation conditions. It is reported that the employment of these newly discovered catalysts show excellent reactivity and ortho-selectivity for diverse classes of aromatic substrates with high isolated yields. Moreover, the catalysts proved to be efficient for a wide number of aliphatic substrates for selective C(sp3)-H bond borylations. Heterocyclic molecules are selectively borylated using the inherently elevated reactivity of the C-H bonds. A number of late-stage C-H functionalization have been described using the same catalysts. Furthermore, we show that one of the catalysts could be used even in open air for the C(sp2)-H and C(sp3)-H borylations enabling the method more general. Preliminary mechanistic studies suggest that the active catalytic intermediate is the Ir(bis)boryl complex, and the attached ligand acts as bidentate ligand. Collectively, this study underlines the discovery of new class of C-H borylation catalysts that should find wide application in the context of C-H functionalization chemistry.
- Chattopadhyay, Buddhadeb,Hassan, Mirja Md Mahamudul,Hoque, Md Emdadul
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supporting information
p. 5022 - 5037
(2021/05/04)
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- Photochemical Activation of Aromatic Aldehydes: Synthesis of Amides, Hydroxamic Acids and Esters
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A cheap, facile and metal-free photochemical protocol for the activation of aromatic aldehydes has been developed. Utilizing thioxanthen-9-one as the photocatalyst and cheap household lamps as the light source, a variety of aromatic aldehydes have been activated and subsequently converted in a one-pot reaction into amides, hydroxamic acids and esters in good to high yields. The applicability of this method was highlighted in the synthesis of Moclobemide, a drug against depression and social anxiety. Extended and detailed mechanistic studies have been conducted, in order to determine a plausible mechanism for the reaction.
- Nikitas, Nikolaos F.,Apostolopoulou, Mary K.,Skolia, Elpida,Tsoukaki, Anna,Kokotos, Christoforos G.
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supporting information
p. 7915 - 7922
(2021/05/03)
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- Process production method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine
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The invention discloses a process production method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine. The method comprises the following steps of: by taking (2R)-2-deoxy-2-fluoro-2-methyl-D-erythropentanoic acid GAMMA-lactone as a raw material, carrying out a
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Paragraph 0034-0035
(2020/09/12)
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- KDM4B INHIBITORS FOR THE TREATMENT OF INFLAMMATORY DISEASES AND DISORDERS
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The invention relates to KDM4B inhibitors, compositions comprising an effective amount of KDM4B inhibitors and methods for treating inflammatory diseases and disorders.
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- Palladium-Catalyzed Chlorocarbonylation of Aryl (Pseudo)Halides Through In Situ Generation of Carbon Monoxide
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An efficient palladium-catalyzed chlorocarbonylation of aryl (pseudo)halides that gives access to a wide range of carboxylic acid derivatives has been developed. The use of butyryl chloride as a combined CO and Cl source eludes the need for toxic, gaseous carbon monoxide, thus facilitating the synthesis of high-value products from readily available aryl (pseudo)halides. The combination of palladium(0), Xantphos, and an amine base is essential to promote this broadly applicable catalytic reaction. Overall, this reaction provides access to a great variety of carbonyl-containing products through in situ transformation of the generated aroyl chloride. Combined experimental and computational studies support a reaction mechanism involving in situ generation of CO.
- Bismuto, Alessandro,Boehm, Philip,Morandi, Bill,Roediger, Sven
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supporting information
p. 17887 - 17896
(2020/08/19)
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- Identification of Anti-Mycobacterial Biofilm Agents Based on the 2-Aminoimidazole Scaffold
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Tuberculosis (TB) remains a significant global health problem for which new therapeutic options are sorely needed. The ability of the causative agent, Mycobacterium tuberculosis, to reside within host macrophages and form biofilm-like communities contributes to the persistent and drug-tolerant nature of the disease. Compounds that can prevent or reverse the biofilm-like phenotype have the potential to serve alongside TB antibiotics to overcome this tolerance, and decrease treatment duration. Using Mycobacterium smegmatis as a surrogate organism, we report the identification of two new 2-aminoimidazole compounds that inhibit and disperse mycobacterial biofilms, work synergistically with isoniazid and rifampicin to eradicate preformed M. smegmatis biofilms in vitro, are nontoxic toward Galleria mellonella, and exhibit stability in mouse plasma.
- Nguyen, T. Vu,Minrovic, Bradley M.,Melander, Roberta J.,Melander, Christian
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p. 927 - 937
(2019/03/26)
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- Palladium-Catalyzed Electrochemical C-H Bromination Using NH4Br as the Brominating Reagent
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The palladium-catalyzed electrochemical C-H bromination of benzamide derivatives under divided cells is developed, in which NH4Br serves as a brominating reagent and electrolyte. The protocol avoids the use of chemical oxidants and provides an alternative method for the synthesis of aryl bromides.
- Yang, Qi-Liang,Wang, Xiang-Yang,Wang, Tong-Lin,Yang, Xiang,Liu, Dong,Tong, Xiaofeng,Wu, Xin-Yan,Mei, Tian-Sheng
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supporting information
p. 2645 - 2649
(2019/04/17)
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- Ligand-Promoted RhIII-Catalyzed Thiolation of Benzamides with a Broad Disulfide Scope
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A ligand-promoted RhIII-catalyzed C(sp2)?H activation/thiolation of benzamides has been developed. Using bidentate mono-N-protected amino acid ligands led to the first example of RhIII-catalyzed aryl thiolation reactions directed by weakly coordinating directing amide groups. The reaction tolerates a broad range of amides and disulfide reagents.
- Kang, Yan-Shang,Zhang, Ping,Li, Min-Yan,Chen, You-Ke,Xu, Hua-Jin,Zhao, Jing,Sun, Wei-Yin,Yu, Jin-Quan,Lu, Yi
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supporting information
p. 9099 - 9103
(2019/06/13)
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- Visible light-induced transformation of aldehydes to esters, carboxylic anhydrides and amides
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A transition metal- and organophotocatalyst free synthesis of esters, carboxylic anhydrides and amides from aldehydes induced by visible-light has been reported. The proposed methodology can be carried out by the use of sunlight or artificial visible light as a blue LED source. The methodology has a very broad applicability and the desired products are obtained in very satisfactory yields.
- Gaspa, Silvia,Raposo, Inês,Pereira, Leonor,Mulas, Gabriele,Ricci, Pier Carlo,Porcheddu, Andrea,De Luca, Lidia
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supporting information
p. 10711 - 10715
(2019/07/15)
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- Decarbonylative Methylation of Aromatic Esters by a Nickel Catalyst
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A Ni-catalyzed decarbonylative methylation of aromatic esters was achieved using methylaluminums as methylating agents. Dimethylaluminum chlorides uniquely worked as the methyl source. Because of the Lewis acidity of aluminum reagents, less reactive alkyl esters could also undergo the present methylation. By controlling the Lewis acidity of aluminum reagents, a chemoselective decarbonylative cross-coupling between alkyl esters and phenyl esters was successful.
- Okita, Toshimasa,Muto, Kei,Yamaguchi, Junichiro
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supporting information
p. 3132 - 3135
(2018/05/28)
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- Pharmaceutical-Oriented Methoxylation of Aryl C(sp 2)-H Bonds using Copper Catalysts
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A pharmaceutical-oriented, copper(II)-catalyzed methoxylation of aryl C(sp 2)-H bonds has been developed. This simple and environmentally benign reaction system occurs efficiently using oxygen as oxidant with broad substrate scope and high functional group tolerance.
- Zhang, Guofu,Zhu, Jianfei,Tong, Chaolai,Ding, Chengrong
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supporting information
p. 1451 - 1454
(2018/05/14)
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- Design, synthesis and docking study of 4-arylpiperazine carboxamides as monoamine neurotransmitters reuptake inhibitors
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Rational drug design method has been used to generate 4-arylpiperazine carboxamides in an effort to develop safer, more potent and effective monoamine neurotransmitters reuptake inhibitors. Out of twenty-seven synthesized compounds, compound 9 displayed potent monoamine neurotransmitter reuptake inhibitory activity against HEK cells transfected with hSERT or hNET. A Surflex-Dock docking model of 9 was also studied.
- Paudel, Suresh,Sun, Ningning,Khadka, Daulat Bikram,Yoon, Goon,Kim, Kyeong-Man,Cheon, Seung Hoon
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p. 4127 - 4135
(2018/07/21)
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- Nickel(ii)-catalyzed tandem C(sp2)-H bond activation and annulation of arenes with gem-dibromoalkenes
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A nickel(ii)/silver(i)-catalyzed tandem C(sp2)-H activation and intramolecular annulation of arenes with dibromoalkenes has been successfully achieved, which offers an efficient approach to the 3-methyleneisoindolin-1-one scaffold. Attractive features of this system include its low cost, ease of operation, and its ability to access a wide range of isoindolinones.
- Shi, Yun,Li, Meng-Sheng,Zhang, Fangdong,Chen, Baohua
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p. 28668 - 28675
(2018/08/29)
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- Synthesis of phthalic acid derivatives: Via Pd-catalyzed alkoxycarbonylation of aromatic C-H bonds with alkyl chloroformates
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A Pd(ii)-catalyzed alkoxycarbonylation of aromatic C-H bonds with alkyl chloroformates has been developed. A broad range of benzamides and alkyl chloroformates are compatible with this protocol. The reaction is operationally simple and scalable. The direct group could be readily removed to access substituted phthalic acid esters (PAEs), 1,2-dibenzyl alcohols and phthalamides. Besides alkoxycarbonylation of benzamide β-C-H bonds, γ-alkoxycarbonylation of 2-phenylacetamide is also feasible.
- Liao, Gang,Chen, Hao-Ming,Shi, Bing-Feng
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supporting information
p. 10859 - 10862
(2018/10/02)
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- Controlled photo-flow oxidative reaction (UV-FOR) platform for ultra-fast phthalide and API synthesis
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An integrated photo-flow oxidative reaction (UV-FOR) platform approach is presented for the synthesis of phthalides. The current protocol is catalyst-free, and uses economical and abundant hydro-carbons and hydrocarbon derivatives such as benzoic acid, benzene, and xylene, as starting materials. The reaction is performed using oxygen as a green oxidant in a time- and labour-efficient manner. This integrated approach has been shown to be successful in making a UV-FOR platform suitable for the on-demand synthesis of phthalides and their further syntheses to 2-arylmethylbenzoic acids and arylogous Michael addition products under relatively mild conditions. The current protocol was further extended to the gram scale synthesis of an ischemic stroke-relevant active pharmaceutical ingredient (API), 3-N-butylphthalide (NBP), in a continuous flow process.
- Aand, Dnyaneshwar,Karekar, Sanjeev,Mahajan, Bhushan,Pawar, Amit B.,Singh, Ajay K.
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supporting information
p. 4584 - 4590
(2018/10/23)
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- Palladium-Catalyzed Decarbonylative Difluoromethylation of Acid Chlorides at Room Temperature
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Methods for the direct synthesis of difluoromethylated arenes are sparse, despite the importance of the difluoromethyl group in medical, agro-, and materials chemistry. A palladium-catalyzed decarbonylative cross-coupling reaction of acid chlorides with a difluoromethyl zinc reagent is achieved to access difluoromethylated compounds. The transformation proceeds at room temperature and shows broad functional group tolerance, thus providing a general and efficient method for decarbonylative difluoromethylation of a wide range of aromatic carboxylic acids.
- Pan, Fei,Boursalian, Gregory B.,Ritter, Tobias
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supporting information
p. 16871 - 16876
(2018/11/23)
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- C-F bond cleavage enabled redox-neutral [4+1] annulation via C-H bond activation
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Using α,α-difluoromethylene alkyne as a nontraditional one-carbon reaction partner, a synthetically novel method for the construction of isoindolin-1-one derivatives via Rh(III)-catalyzed [4+1] annulation reaction is reported. The 2-fold C-F bond cleavage not only enables the generation of desired product under an overall oxidant-free condition but also results in a net migration of carbon-carbon triple bond. In addition, the present reaction protocol exhibits a tolerance of a wide spectrum of functional groups due to the mild reaction conditions employed.
- Wang, Cheng-Qiang,Ye, Lu,Feng, Chao,Loh, Teck-Peng
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supporting information
p. 1762 - 1765
(2017/02/15)
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- Design, synthesis, and biological evaluation of oxazolidone derivatives as highly potent N-acylethanolamine acid amidase (NAAA) inhibitors
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N-Acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme that catalyzes the hydrolysis of endogenous fatty acid ethanolamides (FAEs), such as N-palmitoylethanolamide (PEA). PEA exhibits anti-inflammatory and analgesic activities by engaging peroxisome proliferator-activated receptor α (PPAR-α). Preventing PEA degradation by inhibition of NAAA has been proposed as a novel strategy for the treatment of inflammation and pain. In the present study, we reported the discovery of the oxazolidone derivative as a novel scaffold for NAAA inhibitors, and studied the structure-activity relationship (SAR) by modification of the side chain and terminal lipophilic substituents. The results showed that the link chain length of C5, straight and saturated linkages were the preferred shape patterns for NAAA inhibition. Several nanomolar NAAA inhibitors were described, including 2f, 3h, 3i and 3j with IC50 values of 270 nM, 150 nM, 100 nM and 190 nM, respectively. Enzymatic degradation studies suggested that 2f inhibited NAAA in a selective, noncompetitive and reversible pattern. Moreover, 2f showed high anti-inflammatory and analgesic activities after systemic and oral administration.
- Ren, Jie,Li, Yuhang,Ke, Hongwei,Li, Yanting,Yang, Longhe,Yu, Helin,Huang, Rui,Lu, Canzhong,Qiu, Yan
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p. 12455 - 12463
(2017/03/11)
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- Propargyl Alcohols as One-Carbon Synthons: Redox-Neutral Rhodium(III)-Catalyzed C-H Bond Activation for the Synthesis of Isoindolinones Bearing a Quaternary Carbon
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Herein, rhodium(III)-catalyzed C-H activation/subsequent [4 + 1] cyclization reactions between benzamides and propargyl alcohols are reported in which propargyl alcohols serve as unusual one-carbon units. This title transformation led to a series of isoin
- Wu, Xiaowei,Wang, Bao,Zhou, Yu,Liu, Hong
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supporting information
p. 1294 - 1297
(2017/03/23)
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- General C-H Arylation Strategy for the Synthesis of Tunable Visible Light-Emitting Benzo[a]imidazo[2,1,5-c,d]indolizine Fluorophores
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Herein we report the discovery of the benzo[a]imidazo[2,1,5-c,d]indolizine motif displaying tunable emission covering most of the visible spectrum. The polycyclic core is obtained from readily available amides via a chemoselective process involving Tf2O-mediated amide cyclodehydration, followed by intramolecular C-H arylation. Additionally, these fluorescent heterocycles are easily functionalized using electrophilic reagents, enabling divergent access to varied substitution. The effects of said substitution on the compounds' photophysical properties were rationalized by density functional theory calculations. For some compounds, emission wavelengths are directly correlated to the substituent's Hammett constants. Easily introduced nonconjugated reactive functional groups allow the labeling of biomolecules without modification of emissive properties. This work provides a straightforward platform for the synthesis of new moderately bright fluorescent dyes remarkable for their chemical stability, predictability, and unusually high excitation-emission differential.
- Lévesque, éric,Bechara, William S.,Constantineau-Forget, Léa,Pelletier, Guillaume,Rachel, Natalie M.,Pelletier, Joelle N.,Charette, André B.
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p. 5046 - 5067
(2017/05/24)
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- Amide to Alkyne Interconversion via a Nickel/Copper-Catalyzed Deamidative Cross-Coupling of Aryl and Alkenyl Amides
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A nickel-catalyzed deamidative cross-coupling reaction of amides with terminal alkynes as coupling partners was disclosed. This newly developed methodology allows the direct interconversion of amides to alkynes and enables a facile route for C(sp2)-C(sp) bond formation in a straightforward and mild fashion.
- Srimontree, Watchara,Chatupheeraphat, Adisak,Liao, Hsuan-Hung,Rueping, Magnus
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supporting information
p. 3091 - 3094
(2017/06/23)
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- Palladium-Nanoparticles-Catalyzed Oxidative Annulation of Benzamides with Alkynes for the Synthesis of Isoquinolones
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A novel method to synthesize isoquinolones via oxidative annulation of N-alkoxy benzamides and alkynes using binaphthyl-stabilized palladium nanoparticles (Pd-BNP) as catalyst has been developed. This methodology affords various isoquinolone derivatives in good to excellent yields with high regioselectivities in the presence of air as oxidant. N-Methoxybenzothioamide was also found to undergo oxidative annulation with alkyne successfully and provided a sulfur analogue of isoquinolones in moderate yields. The Pd-BNP catalyst was easily recovered and reused up to four times without any apparent agglomeration. (Figure presented.).
- Sharma, Nidhi,Saha, Rajib,Parveen, Naziya,Sekar, Govindasamy
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supporting information
p. 1947 - 1958
(2017/06/09)
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- Heteroannulation enabled by a bimetallic Rh(III)/Ag(i) relay catalysis: Application in the total synthesis of aristolactam BII
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A redox-neutral bimetallic Rh(iii)/Ag(i) relay catalysis allowed the efficient construction of 3-alkylidene isoindolinones and 3-alkylidene isobenzofuranones. The Rh(iii) catalyst was responsible for the C-H monofluoroalkenylation reaction, whereas the Ag(i) salt was an activator for the follow-up cyclization. The methodology developed was applied as a key step in the rapid total synthesis of the natural product aristolactam BII.
- Ji, Wei-Wei,Lin,Li, Qingjiang,Wang, Honggen
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supporting information
p. 5665 - 5668
(2017/07/07)
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- Iron-catalyzed C-H/N-H activation by triazole guidance: Versatile alkyne annulation
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Iron-catalyzed C-H/N-H functionalizations were achieved by the aid of modular triazole amides. The alkyne annulation allowed for the expedient synthesis of valuable isoquinolone scaffolds with high levels of chemo-, site- and regio-selectivities.
- Cera,Haven,Ackermann
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supporting information
p. 6460 - 6463
(2017/07/10)
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- Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline-Based Histone Deacetylase 8 Selective Inhibitors
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Histone deacetylase 8 (HDAC8) is a promising drug target for multiple therapeutic applications. Here, we describe the modeling, design, synthesis, and biological evaluation of a novel series of C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 inhibitors. Minimization of entropic loss upon ligand binding and use of the unique HDAC8 "open" conformation of the binding site yielded a successful strategy for improvement of both HDAC8 potency and selectivity. The TIQ-based 3g and 3n exhibited the highest 82 and 55 nM HDAC8 potency and 330- and 135-fold selectivity over HDAC1, respectively. Selectivity over other class I isoforms was comparable or better, whereas inhibition of HDAC6, a class II HDAC isoform, was below 50% at 10 μM. The cytotoxicity of 3g and 3n was evaluated in neuroblastoma cell lines, and 3n displayed concentration-dependent cytotoxicity similar to or better than that of PCI-34051. The selectivity of 3g and 3n was confirmed in SH-SY5Y cells as both did not increase the acetylation of histone H3 and α-tubulin. Discovery of the novel TIQ chemotype paves the way for the development of HDAC8 selective inhibitors for therapeutic applications.
- Taha, Taha Y.,Aboukhatwa, Shaimaa M.,Knopp, Rachel C.,Ikegaki, Naohiko,Abdelkarim, Hazem,Neerasa, Jayaprakash,Lu, Yunlong,Neelarapu, Raghupathi,Hanigan, Thomas W.,Thatcher, Gregory R. J.,Petukhov, Pavel A.
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supporting information
p. 824 - 829
(2017/08/16)
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- MnCl2-Catalyzed C?H Alkylations with Alkyl Halides
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C?H alkylations with challenging β-hydrogen-containing alkyl halides were accomplished with sustainable MnCl2 as the catalyst under phosphine-ligand-free conditions. The proximity-induced benzamide C?H activation occurred with ample substrate s
- Liu, Weiping,Cera, Gianpiero,Oliveira, Jo?o C. A.,Shen, Zhigao,Ackermann, Lutz
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supporting information
p. 11524 - 11528
(2017/08/30)
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- Nickel-Catalyzed Decarbonylative Silylation, Borylation, and Amination of Arylamides via a Deamidative Reaction Pathway
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A nickel-catalyzed decarbonylative silylation, borylation, and amination of amides has been developed. This new methodology allows the direct interconversion of amides to arylsilanes, arylboronates, and arylamines and enables a facile route for carbon-heteroatom bond formations in a straightforward and mild fashion.
- Lee, Shao-Chi,Guo, Lin,Yue, Huifeng,Liao, Hsuan-Hung,Rueping, Magnus
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supporting information
p. 2594 - 2598
(2017/10/31)
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- Anhydrides from aldehydes or alcohols via oxidative cross-coupling
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A novel type of metal-free oxidative cross-coupling for the synthesis of symmetrical and mixed anhydrides from aldehydes or benzylic alcohols has been developed. The aldehydes or alcohols were converted in situ into their corresponding acyl chlorides, which were then reacted with an array of carboxylic acids. The methodology has a general applicability, and was successfully employed to prepare either aromatic or aliphatic symmetrical anhydrides and mixed anhydrides, which are very unstable compounds.
- Gaspa, Silvia,Amura, Ida,Porcheddu, Andrea,De Luca, Lidia
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supporting information
p. 931 - 939
(2017/02/10)
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- Metal-free oxidative self-coupling of aldehydes or alcohols to symmetric carboxylic anhydrides
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A metal-free synthesis of symmetrical anhydrides has been developed starting from aldehydes, both aliphatic and aromatic or primary benzylic alcohols. The reaction occurs at room temperature and makes use of trichloroisocyanuric acid (TCCA) as an oxidant providing the desired carboxylic anhydrides in satisfactory yields.
- Gaspa, Silvia,Porcheddu, Andrea,De Luca, Lidia
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supporting information
p. 2533 - 2536
(2017/06/13)
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- A General Cp*CoIII-Catalyzed Intramolecular C?H Activation Approach for the Efficient Total Syntheses of Aromathecin, Protoberberine, and Tylophora Alkaloids
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Herein, we report a Cp*CoIII-catalyzed C?H activation approach as the key step to create highly valuable isoquinolones and pyridones as building blocks that can readily be applied in the total syntheses of a variety of aromathecin, protoberberine, and tylophora alkaloids. This particular C?H activation/annulation reaction was achieved with several terminal as well as internal alkyne coupling partners delivering a broad scope with excellent functional group tolerance. The synthetic applicability of this protocol reported herein was demonstrated in the total syntheses of two Topo-I-Inhibitors and two 8-oxyprotoberberine cores that can be further elaborated into the tetrahydroprotoberberine and the protoberberine alkaloid core. Moreover these building blocks were also transformed to six different tylophora alkaloids in expedient fashion.
- Lerchen, Andreas,Knecht, Tobias,Koy, Maximilian,Daniliuc, Constantin G.,Glorius, Frank
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supporting information
p. 12149 - 12152
(2017/09/13)
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- METHOD FOR PREPARATION OF CARBOXYLIC ACID CHLORIDES FROM METHYL KETONES WITH TWO REAGENTS
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The invention discloses a method for the preparation of carboxylic acid chlorides starting from methyl ketones with a sulfur chloride and a chlorinating reagent.
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Page/Page column 33-34
(2017/01/26)
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- KDM1A INHIBITORS FOR THE TREATMENT OF DISEASE
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Disclosed herein are new compounds and compositions and their application as pharmaceuticals for the treatment of diseases. Methods of inhibition of KDM1A, methods of increasing gamma globin gene expression, and methods to induce differentiation of cancer cells in a human or animal subject are also provided for the treatment of diseases such as acute myelogenous leukemia.
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Paragraph 0327; 0328
(2016/09/26)
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- Synthesis and Biological Investigation of Oxazole Hydroxamates as Highly Selective Histone Deacetylase 6 (HDAC6) Inhibitors
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Histone deacetylase 6 (HDAC6) catalyzes the removal of an acetyl group from lysine residues of several non-histone proteins. Here we report the preparation of thiazole-, oxazole-, and oxadiazole-containing biarylhydroxamic acids by a short synthetic proce
- Senger, Johanna,Melesina, Jelena,Marek, Martin,Romier, Christophe,Oehme, Ina,Witt, Olaf,Sippl, Wolfgang,Jung, Manfred
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p. 1545 - 1555
(2016/03/08)
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- Copper-Catalyzed Divergent Trifluoromethylation/Cyclization of Unactivated Alkenes
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Most of the precedent copper-catalyzed trifluoromethylation reactions of unactivated alkenes concern terminal alkenes, and these processes are terminated in elimination, or nucleophilic addition, or semipinacol rearrangement, or C-H bond functionalization steps. In this study, we develop a trifluoromethylation method for both unactivated terminal and internal alkenes to enable divergent late-stage radical cyclization and achieve high molecular complexity. These cyclizations are well consistent with Baldwin's rule. Furthermore, a kinetic isotope effect (KIE) study and control reactions were conducted, and a plausible mechanism is proposed.
- Zheng, Jing,Deng, Ziyang,Zhang, Yan,Cui, Sunliang
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supporting information
p. 746 - 751
(2016/03/09)
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- Diastereoselective [3+2] Annulation of Aromatic/Vinylic Amides with Bicyclic Alkenes through Cobalt-Catalyzed C-H Activation and Intramolecular Nucleophilic Addition
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A highly diastereoselective method for the synthesis of dihydroepoxybenzofluorenone derivatives from aromatic/vinylic amides and bicyclic alkenes is described. This new transformation proceeds through cobalt-catalyzed C-H activation and intramolecular nucleophilic addition to the amide functional group. Transition-metal-catalyzed C-H activation reactions of secondary amides with alkenes usually lead to [4+2] or [4+1] annulation; to the best of our knowledge, this is the first time that a [3+2] cycloaddition is described in this context. The reaction proceeds under mild conditions and tolerates a wide range of functional groups. Mechanistic studies imply that the C-H bond cleavage may be the rate-limiting step. [3+2] instead of [4+2] or [4+1]: The diastereoselective [3+2] annulation of secondary amides with alkenes proceeds by cobalt-catalyzed C-H activation and intramolecular nucleophilic addition to the amide functional group under mild conditions. Mechanistic studies suggest that the C-H bond cleavage is the rate-limiting step.
- Gandeepan, Parthasarathy,Rajamalli, Pachaiyappan,Cheng, Chien-Hong
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supporting information
p. 4308 - 4311
(2016/04/01)
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- Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis
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Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, a series of new benzohydroxamates were prepared as potent inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by these 3-amidobenzohydroxamates. The newly designed inhibitors were evaluated in screens for enzyme inhibitory activity against schistosome and human HDACs. Twenty-seven compounds were found to be active in the nanomolar range, and some of them showed selectivity toward smHDAC8 over the major human HDACs (1 and 6). The active benzohydroxamates were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Four of these showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.
- Heimburg, Tino,Chakrabarti, Alokta,Lancelot, Julien,Marek, Martin,Melesina, Jelena,Hauser, Alexander-Thomas,Shaik, Tajith B.,Duclaud, Sylvie,Robaa, Dina,Erdmann, Frank,Schmidt, Matthias,Romier, Christophe,Pierce, Raymond J.,Jung, Manfred,Sippl, Wolfgang
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supporting information
p. 2423 - 2435
(2016/04/10)
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- Rh(III)-Catalyzed Redox-Neutral Annulation of Primary Benzamides with Diazo Compounds: Approach to Isoquinolinones
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Reported herein is a Rh-catalyzed redox-neutral annulation of primary benzamides with diazo compounds, representing an efficient and economic protocol to isoquinolinones. The procedure exhibited good functional group tolerability, scalability, and regioselectivity, obviating the need for oxidants, and only environmentally benign N2 and H2O were released. Further utilization of the method provided an alternative route to functionalized isoquinolines.
- Wu, Youzhi,Sun, Peng,Zhang, Kaifan,Yang, Tie,Yao, Hequan,Lin, Aijun
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p. 2166 - 2173
(2016/03/15)
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- Compositions and methods of inhibiting N-acylethanolamine-hydrolyzing acid amidase
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Compounds and pharmaceutical compositions are contemplated that inhibit N-acyl-ethanolamine-hydrolyzing acid amidase (NAAA) to so increase the concentration of the substrate of NAAA, palmitoylethanolamide (PEA). NAAA inhibition is contemplated to be effec
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Page/Page column 10
(2016/05/19)
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- Ligand-Promoted Rh(III)-Catalyzed Coupling of Aryl C-H Bonds with Arylboron Reagents
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Rhodium(III)-catalyzed C-H arylation of arenes with phenylboronic acid pinacol esters has been achieved using a readily removable N-pentafluorophenylbenzamide directing group for the first time. The use of a bidentate phosphine ligand (Binap) significantly increased the yield of the cross-coupling of C-H bonds with organoboron reagents.
- Wang, Huai-Wei,Cui, Pei-Pei,Lu, Yi,Sun, Wei-Yin,Yu, Jin-Quan
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p. 3416 - 3422
(2016/05/19)
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- Mechanisms of action of novel influenza A/M2 viroporin inhibitors derived from hexamethylene amiloride
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The increasing prevalence of influenza viruses with resistance to approved antivirals highlights the need for new anti-influenza therapeutics. Here we describe the functional properties of hexamethylene amiloride (HMA)'derived compounds that inhibit the wildtype and adamantane-resistant forms of the influenza A M2 ion channel. For example, 6-(azepan-1-yl)-N-carbamimidoylnicotinamide (9) inhibits amantadine-sensitive M2 currents with 3- to 6-fold greater potency than amantadine or HMA (IC50 5 0.2 vs. 0.6 and 1.3 μM, respectively). Compound 9 competes with amantadine for M2 inhibition, and molecular docking simulations suggest that 9 binds at site(s) that overlap with amantadine binding. In addition, tert-butyl 4′-(carbamimidoylcarbamoyl)-2′,3-dinitro- [1,1′-biphenyl]-4-carboxylate (27) acts both on adamantanesensitive and a resistantM2variant encoding a serine to asparagine 31 mutation (S31N) with improved efficacy over amantadine and HMA (IC5050.6 μMand4.4mM, respectively).Whereas 9 inhibited in vitro replication of influenza virus encoding wild-type M2 (EC505 2.3 μM), both 27 and tert-butyl 4′-(carbamimidoylcarbamoyl)-2′,3- dinitro-[1,1′-biphenyl]-4-carboxylate (26) preferentially inhibited viruses encoding M2(S31N) (respective EC50 5 18.0 and 1.5 μM). This finding indicates thatHMAderivatives can be designed to inhibit viruses with resistance to amantadine. Our study highlights the potential of HMA derivatives as inhibitors of drug-resistant influenza M2 ion channels.
- Jalily, Pouria H.,Eldstrom, Jodene,Miller, Scott C.,Kwan, Daniel C.,Tai, Sheldon S.-H.,Chou, Doug,Niikura, Masahiro,Tietjen, Ian,Fedida, David
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supporting information
p. 80 - 95
(2016/07/28)
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- Optimization of amino acid thioesters as inhibitors of metallo-β-lactamase L1
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The emergence of antibiotic resistance caused by metallo-β-lactamases (MβLs) is a global public health problem. Recently, we found amino acid thioesters to be a highly promising scaffold for inhibitors of the MβL L1. In order to optimize this series of inhibitors, nine new amino acid thioesters were developed by modifying the substituents on the N-terminus of the thioesters and the groups representing the amino acid side chain. Biological activity assays indicate that all of them are very potent inhibitors of L1 with an IC50value range of 20–600?nM, lower than those of most of the previously reported inhibitors of this scaffold. Analysis of structure–activity relationship reveals that big hydrophobic substituents on the N-terminus and a methionine amino acid side chain improves inhibitory activity of the thioesters. All these inhibitors are able to restore antibacterial activity of a β-lactam antibiotic against Escherichia coli BL21(DE3) cells producing L1 to that against E. coli cells lacking a β-lactamase. Docking studies reveal that a large N-terminal hydrophobic group results in a slightly different binding mode than smaller hydrophobic groups at the same position.
- Liu, Xiao-Long,Yang, Ke-Wu,Zhang, Yue-Juan,Ge, Ying,Xiang, Yang,Chang, Ya-Nan,Oelschlaeger, Peter
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p. 4698 - 4701
(2016/09/13)
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- Synthesis of Functional Fluorescent BODIPY-based Dyes through Electrophilic Aromatic Substitution: Straightforward Approach towards Customized Fluorescent Probes
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Fluorescent materials are widely used in biological and material applications as probes for imaging or sensing; however, their customization is usually complicated without the support of an organic chemistry laboratory. Here, we present a straightforward method for the customization of BODIPY cores, which are among the most commonly used fluorescent probes. The method is based on the formation of a new C?C bond through Friedel–Crafts electrophilic aromatic substitution carried out at room temperature. The method presented can be used to obtain completely customized fluorescent materials in one or two steps from commercially available compounds. Examples of the preparation of fluorescent materials for cell staining and functionalization of silica colloids are also presented.
- Mirri, Giorgio,Schoenmakers, Dani?l C.,Kouwer, Paul H. J.,Verani?, Peter,Mu?evi?, Igor,?tefane, Bogdan
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p. 450 - 454
(2016/10/20)
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- Regiocontrolled Coupling of Aromatic and Vinylic Amides with α-Allenols to Form γ-Lactams via Rhodium(III)-Catalyzed C-H Activation
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A mild, regiocontrolled coupling of aromatic and vinylic amides with α-allenols to form γ-lactams via rhodium(III)-catalyzed C-H activation has been demonstrated. This [4 + 1] annulation reaction provides an efficient method for the synthesis of isoindolinones and 1,5-dihydro-pyrrol-2-ones bearing a tetrasubstituted carbon atom α to the nitrogen atom with good functional group tolerance. The hydroxyl group in the allene substrate is essential in controlling the chemo- and regioselectivity of the reaction probably by coordination interaction with the rhodium catalyst.
- Zhou, Zhi,Liu, Guixia,Lu, Xiyan
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supporting information
p. 5668 - 5671
(2016/11/17)
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- Metal-Free Oxidative Cross Esterification of Alcohols via Acyl Chloride Formation
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A novel metal-free oxidative cross esterification of alcohols has been achieved using trichloroisocyanuric acid as an oxidant. The alcohols were converted in situ into their corresponding acyl chlorides, which were then reacted with primary and secondary aliphatic, benzylic and allylic alcohols and phenols. A wide variety of esters was obtained in satisfactory yields.
- Gaspa, Silvia,Porcheddu, Andrea,De Luca, Lidia
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supporting information
p. 154 - 158
(2016/01/25)
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- Visible-Light-Mediated Synthesis of Amides from Aldehydes and Amines via in Situ Acid Chloride Formation
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An efficient visible-light photocatalysis-based one-pot amide synthesis method was developed; visible-light irradiation of a mixture of an aldehyde, tert-butyl hydrogen peroxide, and N-chlorosuccinimide using a Ru(bpy)3Cl2 photocatalyst afforded an acid chloride, which subsequently reacted with amine to yield the corresponding amide. The reaction was used to synthesize moclobemide and a D3 receptor intermediate.
- Iqbal, Naeem,Cho, Eun Jin
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p. 1905 - 1911
(2016/03/15)
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- METHOD FOR PREPARATION OF CARBOXYLIC ACID CHLORIDES FROM METHYL KETONES
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The invention discloses a method for the preparation of carboxylic acid chlorides starting from methyl ketones with a sulfur chloride.
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Page/Page column 32; 33; 34
(2017/01/02)
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