- Structure-based design, synthesis, and evaluation of inhibitors with high selectivity for PARP-1 over PARP-2
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The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors have lower selectivity to PARP-1 than to PARP-2, so they will inevitably have side effects. Based on the different catalytic domains of PARP-1 and PARP-2, we developed a strategy to design and synthesize highly selective PARP-1 inhibitors. Compounds Y17, Y29, Y31 and Y49 showed excellent PARP-1 inhibition, and their IC50 values were 0.61, 0.66, 0.41 and 0.96 nM, respectively. Then, Y49 (PARP-1 IC50 = 0.96 nM, PARP-2 IC50 = 61.90 nM, selectivity PARP-2/PARP-1 = 64.5) was proved to be the most selective inhibitor of PARP-1. Compounds Y29 and Y49 showed stronger inhibitory effect on proliferation in BRCA1 mutant MX-1 cells than in other cancer cells. In the MDA-MB-436 xenotransplantation model, Y49 was well tolerated and showed remarkable single dose activity. The design strategy proposed in this paper is of far-reaching significance for the further construction of the next generation of selective PARP-1 inhibitors.
- Yu, Jiang,Luo, Lingling,Hu, Tong,Cui, Yating,Sun, Xiao,Gou, Wenfeng,Hou, Wenbin,Li, Yiliang,Sun, Tiemin
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- Selective C-O Bond Reduction and Borylation of Aryl Ethers Catalyzed by a Rhodium-Aluminum Heterobimetallic Complex
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We report the catalytic reduction of a C-O bond and the borylation by a rhodium complex bearing an X-Type PAlP pincer ligand. We have revealed the reaction mechanism based on the characterization of the reaction intermediate and deuterium-labeling experiments. Notably, this novel catalytic system shows steric-hindrance-dependent chemoselectivity that is distinct from conventional Ni-based catalysts and suggests a new strategy for selective C-O bond activation by heterobimetallic catalysis.
- Hara, Naofumi,Nakao, Yoshiaki,Saito, Teruhiko,Seki, Rin
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supporting information
p. 6388 - 6394
(2021/05/31)
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- Non-innocent Radical Ion Intermediates in Photoredox Catalysis: Parallel Reduction Modes Enable Coupling of Diverse Aryl Chlorides
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We describe a photocatalytic system that elicits potent photoreductant activity from conventional photocatalysts by leveraging radical anion intermediates generated in situ. The combination of an isophthalonitrile photocatalyst and sodium formate promotes diverse aryl radical coupling reactions from abundant but difficult to reduce aryl chloride substrates. Mechanistic studies reveal two parallel pathways for substrate reduction both enabled by a key terminal reductant byproduct, carbon dioxide radical anion.
- Chernowsky, Colleen P.,Chmiel, Alyah F.,Wickens, Zachary K.,Williams, Oliver P.,Yeung, Charles S.
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supporting information
p. 10882 - 10889
(2021/07/31)
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- Nickel-Catalyzed Decarbonylative Amination of Carboxylic Acid Esters
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The reaction of carboxylic acid derivatives with amines to form amide bonds has been the most widely used transformation in organic synthesis over the past century. Its utility is driven by the broad availability of the starting materials as well as the kinetic and thermodynamic driving force for amide bond formation. As such, the invention of new reactions between carboxylic acid derivatives and amines that strategically deviate from amide bond formation remains both a challenge and an opportunity for synthetic chemists. This report describes the development of a nickel-catalyzed decarbonylative reaction that couples (hetero)aromatic esters with a broad scope of amines to form (hetero)aryl amine products. The successful realization of this transformation was predicated on strategic design of the cross-coupling partners (phenol esters and silyl amines) to preclude conventional reactivity that forms inert amide byproducts.
- Malapit, Christian A.,Borrell, Margarida,Milbauer, Michael W.,Brigham, Conor E.,Sanford, Melanie S.
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p. 5918 - 5923
(2020/04/08)
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- Ru(II)-Catalyzed Amination of Aryl Fluorides via η6-Coordination
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We developed a Ru/hemilabile-ligand-catalyzed nucleophilic aromatic substitution (SNAr) of aryl fluorides as the limiting reagents. Significant ligand enhancement was demonstrated by the engagement of both electron-rich and neutral arenes in the SNAr amination without using excess arenes. Preliminary mechanistic studies revealed that the nucleophilic substitution proceeds on a η6-complex of the Ru catalyst and the substrate, and the hemilabile ligand facilitates dissociation of products from the metal center.
- Kang, Qi-Kai,Li, Yuntong,Lin, Yunzhi,Shi, Hang
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supporting information
p. 3706 - 3711
(2020/03/11)
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- Para-selective borylation of monosubstituted benzenes using a transient mediator
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Herein, we conceptualized a transient mediator approach that has the capability of para-selective C-H functionalization of monosubstituted aromatics. This approach is enabled by in situ generation of a versatile sulfonium salt via highly electrophilic phenoxathiine or thianthrene dication intermediate which can be readily generated from its sulfoxide with trifluoromethanesulfonic anhydride. Preliminary mechanistic study implied that the remarkable para selectivity might be related to the incredible electrophilicity of thianthrene dication intermediate. The versatility of this approach was demonstrated via para-borylation of various monosubstituted simple aromatics combining the sulfonium salt formation with further photocatalyzed transformation.
- Wu, Jie,Wang, Zengwei,Chen, Xiao-Yue,Wu, Yichen,Wang, Daoming,Peng, Qian,Wang, Peng
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p. 336 - 340
(2019/12/09)
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- Pd-Catalyzed Site-Selective Borylation of Simple Arenes via Thianthrenation?
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Site-selective borylation of simple arenes was realized in one pot via an electrophilic thianthrenation/Pd-catalyzed borylation sequence. The key to achieve this operatically simple process is the use of Pd catalysis, which could tolerate the solvent and acidic conditions used in the thianthrenation step. This protocol features mild conditions, broad functional group tolerance, and simple manipulations, and is suitable for late-stage functionalization of a wide range of pharmaceuticals and complex bioactive molecules.
- Chen, Xiao-Yue,Huang, Yu-Hao,Zhou, Jian,Wang, Peng
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p. 1269 - 1272
(2020/08/13)
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- Discovery, Optimization, and Target Identification of Novel Potent Broad-Spectrum Antiviral Inhibitors
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Viral infections are increasing and probably long-lasting global risks. In this study, a chemical library was exploited by phenotypic screening to discover new antiviral inhibitors. After optimizations from hit to lead, a novel potent small molecule (RYL-634) was identified, showing excellent broad-spectrum inhibition activity against various pathogenic viruses, including hepatitis C virus, dengue virus, Zika virus, chikungunya virus, enterovirus 71, human immunodeficiency virus, respiratory syncytial virus, and others. The mechanism of action and potential targets of RYL-634 were further explored by the combination of activity-based protein profiling and other techniques. Finally, human dihydroorotate dehydrogenase was validated as the major target of RYL-634. We did not observe any mutant resistance under our pressure selections with RYL-634, and it had a strong synergistic effect with some Food and Drug Administration-approved drugs. Hence, there is great potential for developing new broad-spectrum antivirals based on RYL-634.
- Yang, Yiqing,Cao, Lin,Gao, Hongying,Wu, Yue,Wang, Yaxin,Fang, Fang,Lan, Tianlong,Lou, Zhiyong,Rao, Yu
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p. 4056 - 4073
(2019/05/06)
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- Nickel-Catalyzed Decarboxylation of Aryl Carbamates for Converting Phenols into Aromatic Amines
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Herein, we describe a new catalytic approach to accessing aromatic amines from an abundant feedstock, namely phenols. The most reliable catalytic method for converting phenols to aromatic amines uses an activating group, such as a trifluoromethane sulfonyl group. However, this activating group is eliminated as a leaving group during the amination process, resulting in significant waste. Our nickel-catalyzed decarboxylation reaction of aryl carbamates forms aromatic amines with carbon dioxide as the only byproduct. As this amination proceeds in the absence of free amines, a range of functionalities, including a formyl group, are compatible. A bisphosphine ligand immobilized on a polystyrene support (PS-DPPBz) is key to the success of this reaction, generating a catalytic species that is significantly more active than simple nonsupported variants.
- Nishizawa, Akihiro,Takahira, Tsuyoshi,Yasui, Kosuke,Fujimoto, Hayato,Iwai, Tomohiro,Sawamura, Masaya,Chatani, Naoto,Tobisu, Mamoru
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supporting information
p. 7261 - 7265
(2019/05/16)
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- Palladium-Catalyzed Decarbonylative Borylation of Carboxylic Acids: Tuning Reaction Selectivity by Computation
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Decarbonylative borylation of carboxylic acids is reported. Carbon electrophiles are generated directly after reagent-enabled decarbonylation of the in situ accessible sterically-hindered acyl derivative of a carboxylic acid under catalyst controlled conditions. The scope and the potential impact of this method are demonstrated in the selective borylation of a variety of aromatics (>50 examples). This strategy was used in the late-stage derivatization of pharmaceuticals and natural products. Computations reveal the mechanistic details of the unprecedented C?O bond activation of carboxylic acids. By circumventing the challenging decarboxylation, this strategy provides a general synthetic platform to access arylpalladium species for a wide array of bond formations from abundant carboxylic acids. The study shows a powerful combination of experiment and computation to predict decarbonylation selectivity.
- Liu, Chengwei,Ji, Chong-Lei,Hong, Xin,Szostak, Michal
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supporting information
p. 16721 - 16726
(2018/11/30)
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- Palladium-Catalyzed ipso-Borylation of Aryl Sulfides with Diborons
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A catalytic Miyaura-type ipso-borylation of aryl sulfides with diboron reagents has been achieved, providing arylboronate esters of synthetic use. The key conditions to transform inherently reluctant C-S bonds into C-B bonds include a palladium-NHC (N-heterocyclic carbene) precatalyst, bis(pinacolato)diboron, and lithium hexamethyldisilazide. This protocol is applicable to a reasonable range of aryl alkyl sulfides. Twofold borylation was observed in the reaction of diphenyl sulfide.
- Bhanuchandra,Baralle, Alexandre,Otsuka, Shinya,Nogi, Keisuke,Yorimitsu, Hideki,Osuka, Atsuhiro
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p. 2966 - 2969
(2016/07/06)
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- Rhodium-Catalyzed ipso-Borylation of Alkylthioarenes via C-S Bond Cleavage
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Rhodium-catalyzed transformation of alkyl aryl sulfides into arylboronic acid pinacol esters via C-S bond cleavage is reported. In combination with transition-metal-catalyzed sulfanyl group-guided regioselective C-H borylation reactions of alkylthioarenes, this method allows the synthesis of a diverse range of multisubstituted arenes.
- Uetake, Yuta,Niwa, Takashi,Hosoya, Takamitsu
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p. 2758 - 2761
(2016/06/15)
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- The method for producing the phenyl boronic acid ester
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PROBLEM TO BE SOLVED: To provide a method for producing phenylboronic acid esters in good yield from diborons and aryl halides by using a nickel catalyst and a base. SOLUTION: In the method for producing phenylboronic acid esters represented by general formula (3), wherein A is an ethylene group or the like which may be substituted by a methyl group, R1is a fluorine atom or the like, and m is an integer of 0-5; diborons and a chlorobenzene derivative are reacted with each other by using a trimethylphosphine coordinated nickel catalyst and alkoxides. COPYRIGHT: (C)2013,JPOandINPIT
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Paragraph 0107; 0108
(2018/09/26)
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- SPIRO-SUBSTITUTED OXINDOLE DERIVATIVES HAVING AMPK ACTIVITY
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The present invention relates to compounds of formula (I), which have valuable pharmacological properties, in particular are activators of AMPK and which are therefore useful in the treatment of certain disorders that can be prevented or treated by activation of this receptor. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.
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Page/Page column 79
(2015/01/07)
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- Kinase scaffold repurposing for neglected disease drug discovery: Discovery of an efficacious, lapatanib-derived lead compound for trypanosomiasis
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Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei. Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns b
- Patel, Gautam,Karver, Caitlin E.,Behera, Ranjan,Guyett, Paul J.,Sullenberger, Catherine,Edwards, Peter,Roncal, Norma E.,Mensa-Wilmot, Kojo,Pollastri, Michael P.
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supporting information
p. 3820 - 3832
(2013/06/27)
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- Isocytosine-based inhibitors of xanthine oxidase: Design, synthesis, SAR, PK and in vivo efficacy in rat model of hyperuricemia
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Structure-activity relationship studies were carried out for lead generation following structure-guided design approach from an isocytosine scaffold identified earlier for xanthine oxidase inhibition. A 470-fold improvement in in vitro IC50 was obtained in the process. Five most potent compounds with nanomolar IC50 values were selected for pharmacokinetics and in vivo experiments. The best compound showed good in vivo activity when administered intraperitoneally but was not active by oral route. The results suggest that improvement in oral exposure could improve the in vivo efficacy of this series.
- Khanna, Smriti,Burudkar, Sandeep,Bajaj, Komal,Shah, Pranay,Keche, Ashish,Ghosh, Usha,Desai, Avani,Srivastava, Ankita,Kulkarni-Almeida, Asha,Deshmukh, Nitin J.,Dixit, Amol,Brahma, Manoja K.,Bahirat, Umakant,Doshi, Lalit,Nemmani, Kumar V.S.,Tannu, Prashant,Damre, Anagha,B-Rao, Chandrika,Sharma, Rajiv,Sivaramakrishnan
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p. 7543 - 7546
(2013/02/22)
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- NiCl2(PMe3)2-catalyzed borylation of aryl chlorides
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The cross-coupling of aryl chlorides and bis(pinacolato)diboron was achieved using NiCl2(PMe3)2 catalyst in the presence of metal 2,2,2-trifluoroethoxide. The catalyst smoothly provided the desired products regardless of a variety of functional groups and substituted positions.
- Yamamoto, Tetsuya,Morita, Tomoyuki,Takagi, Jun,Yamakawa, Tetsu
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supporting information; experimental part
p. 5766 - 5769
(2012/01/06)
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- COMPOUNDS
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The invention relates to novel aminothiazole derivatives which are inhibitors of the transforming growth factor, ("TGF")-? signalling pathway, in particular, the phosphorylation of smad2 or smad3 by the TGF-β type I or activin-like kinase ("ALK")-5 receptor, methods for their preparation and their use in medicine, specifically in the treatment and prevention of a disease state mediated by this pathway.
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