- SUBSTITUTED BICYCLIC COMPOUNDS AS FARNESOID X RECEPTOR MODULATORS
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Disclosed are compounds of Formula (I): or a stereoisomer, a tautomer, or a salt or solvate thereof, wherein Q is C2-6 alkenyl or C2-6 alkynyl, each substituted with zero to 2 R1; and the other variables are as defined herein. These compounds modulate the activity of farnesoid X receptor (FXR), for example, as agonists. Also disclosed are pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.
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Page/Page column 188-190
(2020/08/28)
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- Catalyst shuttling enabled by a thermoresponsive polymeric ligand: Facilitating efficient cross-couplings with continuously recyclable ppm levels of palladium
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A polymeric monophosphine ligand WePhos has been synthesized and complexed with palladium(ii) acetate [Pd(OAc)2] to generate a thermoresponsive pre-catalyst that can shuttle between water and organic phases, with the change being regulated by temperature. The structure of the polymeric ligand was confirmed with matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) mass spectrometry and size-exclusion chromatography (SEC) analysis, as well as nuclear magnetic resonance (NMR) measurements. This polymeric metal complex enables highly efficient Pd-catalyzed cross-couplings and tandem reactions using 50 to 500 ppm palladium, and this can facilitate reactions that are tolerant to a broad spectrum of (hetero)aryl substrates and functional groups, as demonstrated with 73 examples with up to 99% isolated yields. Notably, 97% Pd remained in the aqueous phase after 10 runs of catalyst recycling experiments, as determined via inductively coupled plasma-atomic emission spectrometry (ICP-AES) measurements, indicating highly efficient catalyst transfer. Furthermore, a continuous catalyst recycling approach has been successfully developed based on flow chemistry in combination with the catalyst shuttling behavior, allowing Suzuki-Miyaura couplings to be conducted at gram-scales with as little as 10 ppm Pd loading. Given the significance of transition-metal catalyzed cross-coupling and increasing interest in sustainable chemistry, this work is an important step towards the development of a responsive catalyst, in addition to having high activity, by tuning the structures of the ligands using polymer science.
- Wang, Erfei,Chen, Mao
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p. 8331 - 8337
(2019/09/30)
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- An N-heterocyclic carbene-functionalised covalent organic framework with atomically dispersed palladium for coupling reactions under mild conditions
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Covalent organic frameworks (COFs) are a new class of crystalline porous materials that could function as excellent scaffolds for heterogeneous catalysts. Herein, we report a functionalised COF (COF-NHC) using N-heterocyclic carbene (NHC) as a monomer building block via a facile ionothermal strategy. The simple and easily prepared imine-linked COF-NHC possessed two coordination sites (NHC and amine), which could fix the active component (Pd) tightly in COF, leading to atomically dispersed Pd in a heterogeneous catalyst. The as-prepared Pd@COF-NHC showed high stability in the Suzuki-Miyaura coupling reaction of arylboronic acids and aryl halides in aqueous media at room temperature, and could be easily recycled and reused multiple times without the loss of catalytic activity. Moreover, C-C coupling reactions could be accomplished using triarylbismuth reagents in ethanol aqueous solutions with high yields.
- Yang, Junjuan,Wu, Yuanyuan,Wu, Xiaowei,Liu, Wenjing,Wang, Yaofang,Wang, Junwen
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supporting information
p. 5267 - 5273
(2019/10/11)
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- Design, synthesis, and structure-activity relationship of 7-propanamide benzoxaboroles as potent anticancer agents
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Benzoxaboroles, as a novel class of bioactive molecules with unique physicochemical properties, have been shown to possess excellent antimicrobial activities with tavaborole approved in 2014 as an antifungal drug. Although urgently needed, the investigation of benzoxaboroles as anticancer agents has been lacking so far. In this study, we report the design, synthesis, and anticancer structure-activity relationship of a series of 7-propanamide benzoxaboroles. Compounds 103 and 115 showed potent activity against ovarian cancer cells with IC50 values of 33 and 21 nM, respectively. Apoptosis was induced by these compounds and colony formation was effectively inhibited. Furthermore, they also showed excellent efficacy in ovarian tumor xenograft mouse model.
- Zhang, Jiong,Zhang, Jinyi,Hao, Guiyun,Xin, Weixiang,Yang, Fei,Zhu, Mingyan,Zhou, Huchen
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p. 6765 - 6784
(2019/08/20)
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- FNEW ACTIVATORS OF SIRT1 ENZYME FOR THE TREATMENT OF CARDIOVASCULAR AND CARDIOMETABOLIC PATHOLOGIES
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This invention describes a class of compounds able to activate the human SIRT1 enzyme and regulate many metabolic functions. This invention relates to compounds that can be employed in medical applications, specifically for the treatment or prevention of cardiometabolic diseases, such as diabetes, and of cardiovascular disorders, such as coronaropathy, heart failure and atherosclerosis.
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Page/Page column 13; 17; 30-31
(2019/09/12)
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- Poly(: O -aminothiophenol)-stabilized Pd nanoparticles as efficient heterogenous catalysts for Suzuki cross-coupling reactions
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Poly(o-aminothiophenol) (PATP)-stabilized Pd nanoparticles with Pd nanoparticles embedded in a polymer matrix have been obtained through a facile one-step route by mixing o-aminothiophenol monomer and Pd(NO3)2 in an acidic aqueous solution without additional template or surfactant. The redox reaction between o-aminothiophenol and Pd(NO3)2 leads to the simultaneous formation of a PATP polymer and Pd nanoparticles. The PATP-stabilized Pd nanoparticles have been characterized by TEM, FTIR, XRD, ICP-MS and XPS. Catalytic results showed that PATP-stabilized Pd nanoparticles were highly stable and active catalysts for Suzuki cross-coupling reactions, where high yields could be achieved with arylboronic acid and aryl halides bearing a variety of substituents.
- Chen, Yuan,Wang, Minggui,Zhang, Long,Liu, Yan,Han, Jie
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p. 47104 - 47110
(2017/10/16)
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- Cobalt-Catalyzed Biaryl Couplings via C-F Bond Activation in the Absence of Phosphine or NHC Ligands
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A highly general and selective Co-catalyzed biaryl coupling through C-F cleavage under phosphine or NHC-free conditions was described. A broad range of aryl fluorides including unactivated fluorides as well as those with sensitive functionalities could couple with various Ti(OEt)4-mediated aryl Grignard reagents with high selectivity under the catalysis of CoCl2/DMPU. Importantly, selective C-F bond activation couplings between two types of fluorines (difluorinated aromatics and on two different coupling partners) and in the presence of C-Cl or C-Br bonds could also be achieved.
- Wei, Juan,Liu, Kun-Ming,Duan, Xin-Fang
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p. 1291 - 1300
(2017/02/10)
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- Iodine-Promoted Semmler–Wolff Reactions: Step-Economic Access to meta-Substituted Primary Anilines via Aromatization
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An atom- and step-economic access to an array of unprotected meta-substituted primary anilines was disclosed using the Semmler–Wolff reaction, promoted by molecular iodine. Therein, noble metal catalysts and inert atmosphere are unnecessary while the forcing reaction conditions and the lengthy synthesis can be avoided. The synthetic utility of this approach is evident in the de novo syntheses of three bioactive molecules with good total yields.
- Wang, Shi-Ke,You, Xia,Zhao, Da-Yuan,Mou, Neng-Jie,Luo, Qun-Li
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p. 11757 - 11760
(2017/09/07)
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- 3-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations
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Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase H arises from the general lack of selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein the synthesis and biochemical evaluations of three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective RNase H inhibition. Biochemical studies showed the two subtypes with an N-1 methyl group (9 and 10) inhibited RNase H in low micromolar range without siginificantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype 11 inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1 INST assay and no significant cytotoxicity in the cell viability assay, suggesting that it may be amenable to further structure-activity relationship (SAR) for identifying RNase H inhibitors with antiviral activity.
- Tang, Jing,Liu, Feng,Nagy, Eva,Miller, Lena,Kirby, Karen A.,Wilson, Daniel J.,Wu, Bulan,Sarafianos, Stefan G.,Parniak, Michael A.,Wang, Zhengqiang
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p. 2648 - 2659
(2016/04/10)
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- Pd-catalyzed Semmler-Wolff reactions for the conversion of substituted cyclohexenone oximes to primary anilines
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Homogeneous Pd catalysts have been identified for the conversion of cyclohexenone and tetralone O-pivaloyl oximes to the corresponding primary anilines and 1-aminonaphthalenes. This method is inspired by the Semmler-Wolff reaction, a classic method that exhibits limited synthetic utility owing to its forcing conditions, narrow scope, and low product yields. The oxime N-O bond undergoes oxidative addition to Pd0(PCy3)2, and the product of this step has been characterized by X-ray crystallography and shown to undergo dehydrogenation to afford the aniline product.
- Hong, Wan Pyo,Iosub, Andrei V.,Stahl, Shannon S.
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supporting information
p. 13664 - 13667
(2013/10/01)
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- Investigations on the 1-(2-biphenyl)piperazine motif: Identification of new potent and selective ligands for the serotonin7 (5-HT7) receptor with agonist or antagonist action in vitro or ex vivo
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Here we report the design, synthesis, and 5-HT7 receptor affinity of a set of 1-(3-biphenyl)- and 1-(2-biphenyl)piperazines. The effect on 5-HT7 affinity of various substituents on the second (distal) phenyl ring was analyzed. Several compounds showed 5-HT7 affinities in the nanomolar range and >100-fold selectivity over 5-HT1A and adrenergic α1 receptors. 1-[2-(4-Methoxyphenyl)phenyl] piperazine (9a) showed 5-HT7 agonist properties in a guinea pig ileum assay but blocked 5-HT-mediated cAMP accumulation in 5-HT7- expressing HeLa cells.
- Lacivita, Enza,Patarnello, Daniela,Stroth, Nikolas,Caroli, Antonia,Niso, Mauro,Contino, Marialessandra,De Giorgio, Paola,Di Pilato, Pantaleo,Colabufo, Nicola A.,Berardi, Francesco,Perrone, Roberto,Svenningsson, Per,Hedlund, Peter B.,Leopoldo, Marcello
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supporting information; experimental part
p. 6375 - 6380
(2012/10/08)
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- A preparatively convenient ligand-free catalytic PEG 2000 suzuki-miyaura coupling
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A ligand-free Suzuki-Miyaura reaction for the cross-coupling of aryl and heteroaryl bromides with aryl and heteroarylboronic acids has been developed utilizing catalytic polyethylene glycol 2000 (PEG 2000). This preparatively convenient system afforded the corresponding cross-coupled products in good to excellent isolated yields after a simple aqueous workup. Transmission electron microscopy (TEM) analysis of the Pd-PEG 2000 catalyst system revealed in situ-generated palladium nanoparticles after only 1 min of reaction.
- Razler, Thomas M.,Hsiao, Yi,Qian, Feng,Fu, Ruiling,Khan, Rana Kashif,Doubleday, Wendel
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supporting information; experimental part
p. 1381 - 1384
(2009/06/28)
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- Correspondence between Molecular Functionality and Crystal Structures. Supramolecular Chemistry of a Family of Homologated Aminophenols
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The crystal structures and packing features of a family of 13 aminophenols, or supraminols, are analyzed and correlated. These compounds are divided into three groups: (a) compounds 1-5 with methylene spacers of the general type HO-C6H4-(CH2)n- C6H 4-NH2 (n = 1 to 5) and both OH and NH2 in a para position; (b) compounds la, 2a, 2b, 2c, and 3a in which one or more of the methylene linkers in 1 to 3 are exchanged with an S-atom; and (c) compounds 2d, 1b, and 6a prepared with considerations of crystal engineering and where the crystal structures may be anticipated on the basis of structures 1-5, 1a, 2a, 2b, 2c, and 3a. These 13 aminols can be described in terms of three major supramolecular synthons based on hydrogen bonding between OH and NH2 groups: the tetrameric loop or square motif, the infinite N(H)O chain, and β-As sheet. These three synthons are not completely independent of each other but interrelate, with the structures tending toward the more stable β-As sheet in some cases. Compounds 1-5 show an alternation in melting points, and compounds with n = even exhibit systematically higher melting points compared to those with n = odd. The alternating melting points are reflected in, and explained by, the alternation in the crystal structures. The n = odd structures tend toward the β-As sheet as n increases and can be considered as a variable series whereas for n = even, the β-As sheet is invariably formed constituting a fixed series. Substitution of a methylene group by an isosteric S-atom may causes a change in the crystal structure. These observations are rationalized in terms of geometrical and chemical effects of the functional groups. This study shows that even for compounds with complex crystal structures the packing may be reasonably anticipated provided a sufficient number of examples are available.
- Vangala, Venu R.,Bhogala, Balakrishna R.,Dey, Archan,Desiraju, Gautam R.,Broder, Charlotte K.,Smith, Philip S.,Mondal, Raju,Howard, Judith A. K.,Wilson, Chick C.
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p. 14495 - 14509
(2007/10/03)
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- Palladium-catalyzed coupling of functionalized bromoarenes to a polystyrene-bound aryl tributylstannane
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The Stille reaction with a polystyrene-bound stannyl component, catalyzed by a palladacycle complex, provides a convenient and clean method for the synthesis of substituted biaryls on the resin. Several functional groups useful for the construction of supported polydentate amino alcohols were successfully introduced.
- Brody, Marcus S.,Finn
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p. 415 - 418
(2007/10/03)
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- Palladium-catalyzed dehydrative aromatization of cyclohexenone oximes to anilines
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Cyclohexenone oximes were smoothly dehydrated to the corresponding anilines by the catalysis of palladium on carbon.
- Matsumoto,Tomizuka,Suzuki
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p. 1441 - 1446
(2007/10/02)
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