- Thiophene Modulated BODIPY Dye as a Light Harvester
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A new BODIPY dye with terthiophene branched is configured by Sonogashira coupling and fully characterized by NMR and MS. In general organic solvents, it emits typical green fluorescence ranging in 513-518 nm, like most BODIPY analogues. The terthiophene substitution is greatly improved and the emission peak does not sensitive to the polarity environment. More importantly, the terthiophene plays the role of antenna, harvesting the 340 nm’s excitation energy and transferring the energy to BODIPY efficiently. Even though the molar extinction coefficient in 340 nm is lower than that of maximum absorption, it can enlarge the pseudo Stoke’s shift to ~170 nm, well separating the excitation and emission. In film, the emission shifted to 562 nm due to the polymer chain dissipation part of the energy. It shifted further to 585 nm in solid. The branched terthiophene configures a twisted molecular conformation, which avoids the dye regular packing. Highly emission, excellent solubility and stability constitute the general character of the thiophene attached BIDIPY dye.
- Li, Xiaochuan,Liao, Meifei,Sun, Jia,Heo, Gisu,Son, Young-A
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- A BODIPY-based highly emissive dye with thiophene-based branch harvesting the light
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A novel BODIPY-based dye with highly emissive character was configured by Sonogashira coupling and routinely characterized by NMR and MS technology. The emission of dye was investigated in solution/film/solid and shows intensive emission. In solution, the emission peak appeared around 510?nm with little influence by the polar environment. The terthiophene plays an effective antenna effect, harvesting the light and transferring the energy to BODIPY. The pseudo Stoke's shift enlarged to ~170?nm in solution. In film, the emission peak shifted to 563?nm in polycarbonate matrix. And it shifted further to 585?nm in solid due to the highly twisted structure, which avoided closely regular-tight packing. The dye rendered an intense fluorescence, good optothermal stability, and high fluorescence quantum yield (0.55). The solid emission showed highly red emission with Commission Internationale de L'Eclairage (CIE) coordinates of (X = 0.69, Y = 0.31). Thus, the synthesized dye is idea candidate for emitting materials.
- Li, Xiaochuan,Han, Yujie,Kim, Myeong Jin,Son, Young-A
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- Fluorogenic Trp(redBODIPY) cyclopeptide targeting keratin 1 for imaging of aggressive carcinomas
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Keratin 1 (KRT1) is overexpressed in squamous carcinomas and associated with aggressive pathologies in breast cancer. Herein we report the design and preparation of the first Trp-based red fluorogenic amino acid, which is synthetically accessible in a few steps and displays excellent photophysical properties, and its application in a minimally-disruptive labelling strategy to prepare a new fluorogenic cyclopeptide for imaging of KRT1+ cells in whole intact tumour tissues.
- Subiros-Funosas, Ramon,Ho, Vivian Cheuk Lam,Barth, Nicole D.,Mendive-Tapia, Lorena,Pappalardo, Morena,Barril, Xavier,Ma, Ruoyu,Zhang, Cheng-Bin,Qian, Bin-Zhi,Sintes, Miquel,Ghashghaei, Ouldouz,Lavilla, Rodolfo,Vendrell, Marc
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- Synthesis and radioiodination of some 9-aminoacridine derivatives
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Derivatives of 9-aminoacridine, namely N-[ω-(acridin-9-yl-amino) alkyl]-3-(trimethylstannyl)benzamides (1), where the alkyl group is propyl (1a) and octyl (1b), and 2-(acridin-9-ylamino)-3-(4-hydroxyphenyl)propionic acid (2), have been synthesized with the aim to use them as precursors in the syntheses of radiolabeled DNA intercalators for biological experiments. It was observed that compounds 1a and 1b can exist in two isomeric forms at room temperature. Radioiodination of the two benzamides 1a and 1b was carried out with the Auger-emitting nuclide 125I by exchange of the trimethylstannyl group. The optimal conditions for radioiodination of the octyl derivative 1b were established and the labeling yield was found to be as high as 92%, according to TLC analysis in model experiments. Purification of the radioiodinated products gave radiochemical yields of 56% for the propyl and 74% for the octyl compound. The amino acid 2 was directly labeled with 125I at the ortho position to the hydroxyl group by taking advantage of the activated ring. The experiment afforded a very high labeling yield (92%). Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Ghirmai, Senait,Mume, Eskender,Henssen, Cecile,Ghaneolhusseini, Hadi,Lundqvist, Hans,Tolmachev, Vladimir,Sjoeberg, Stefan,Orlova, Anna
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- Lead derivatization of ethyl 6-bromo-2-((dimethylamino)methyl)-5-hydroxy-1-phenyl-1H-indole-3-carboxylate and 5-bromo-2-(thiophene-2-carboxamido) benzoic acid as FabG inhibitors targeting ESKAPE pathogens
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Our previous studies on FabG have identified two compounds 5-bromo-2-(thiophene-2-carboxamido) benzoic acid (A) and ethyl 6-bromo-2-((dimethylamino)methyl)-5-hydroxy-1-phenyl-1H-indole-3-carboxylate(B) as best hits with allosteric mode of inhibition. FabG is an integral part of bacterial fatty acid biosynthetic system FAS II shown to be an essential gene in most ESKAPE Pathogens. The current work is focussed on lead expansion of these two hit molecules which ended up with forty-three analogues (twenty-nine analogues from lead compound A and fourteen compounds from lead compound B). The enzyme inhibition studies revealed that compound 15 (effective against EcFabG, AbFabG, StFabG, MtFabG1) and 19 (inhibiting EcFabG and StFabG) had potency of broad-spectrum inhibition on FabG panel.
- Varakala, Saiprasad Dasugari,Reshma, Rudraraju Srilakshmi,Schnell, Robert,Dharmarajan, Sriram
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- Nickel-mediated C(sp2)-H amidation in synthesis of secondary sulfonamides via sulfonyl azides as amino source
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In this paper, Ni(II)- Catalyzed ortho-amidation of C(sp2)-H bond with sulfonyl azides directed by (quinolin-8-yl) amine (AQ-amine) is described. The method provides a straightforward method for the synthesis of sulfonamides from available sulfonyl azides via the transition-metal-catalyzed C(sp2)-N bond forming reaction. The amidation reactions exhibit high functional group compatibility, which might proceed a Ni(III)/Ni(I) catalytic cycle. We also applied sulfonamide compound in OLEDs, which exhibits the certain application potential in OLEDs field.
- Xu, Peng,Ding, Peng-Fei,Zhang, Mei-Qi,Xia, Yu-Shi,Xie, Ting
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supporting information
(2021/02/16)
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- Highly regioselective and stereoselective synthesis of C-Aryl glycosidesvianickel-catalyzedortho-C-H glycosylation of 8-aminoquinoline benzamides
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C-Aryl glycosides are of high value as drug candidates. Here a novel and cost-effective nickel catalyzedortho-CAr-H glycosylation reaction with high regioselectivity and excellent α-selectivity is described. This method shows great functional group compatibility with various glycosides, showing its synthetic potential. Mechanistic studies indicate that C-H activation could be the rate-determining step.
- Chen, Xi,Ding, Ya-Nan,Gou, Xue-Ya,Liang, Yong-Min,Luan, Yu-Yong,Niu, Zhi-Jie,Shi, Wei-Yu,Zhang, Zhe,Zheng, Nian
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supporting information
p. 8945 - 8948
(2021/09/10)
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- Synthesis of N-trifluoromethyl amides from carboxylic acids
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Found in biomolecules, pharmaceuticals, and agrochemicals, amide-containing molecules are ubiquitous in nature, and their derivatization represents a significant methodological goal in fluorine chemistry. Trifluoromethyl amides have emerged as important functional groups frequently found in pharmaceutical compounds. To date, there is no strategy for synthesizing N-trifluoromethyl amides from abundant organic carboxylic acid derivatives, which are ideal starting materials in amide synthesis. Here, we report the synthesis of N-trifluoromethyl amides from carboxylic acid halides and esters under mild conditions via isothiocyanates in the presence of silver fluoride at room temperature. Through this strategy, isothiocyanates are desulfurized with AgF, and then the formed derivative is acylated to afford N-trifluoromethyl amides, including previously inaccessible structures. This method shows broad scope, provides a platform for rapidly generating N-trifluoromethyl amides by virtue of the diversity and availability of both reaction partners, and should find application in the modification of advanced intermediates.
- Flavell, Robert R.,Liu, Jianbo,Parker, Matthew F. L.,Toste, F. Dean,Wang, Sinan,Wilson, David M.
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supporting information
p. 2245 - 2255
(2021/08/12)
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- Synthesis of new alkenyl iodobenzoate derivatives via Kharasch-Sosnovsky reaction using tert-butyl iodo benzoperoxoate and copper (I) iodide
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Abstract: The synthesis of new alkenyl iodobenzoate derivatives as allylic esters was investigated via the reaction of tert-butyl iodobenzoperoxoate with alkenes in the presence of copper salts. The best result was obtained using tert-butyl-iodobenzoperoxoate in the presence of copper (I) iodide (5?mol%) in refluxing acetonitrile with good yield (92%) in 32?h. The structure of peresters and alkenyl iodobenzoate derivatives were characterized on the basis of their FT-IR, 1HNMR, 13CNMR, and Mass spectra. Graphic abstract: The preparation of new iodo-allylic esters from alkenes in the presence of copper salts in good to excellent yields is reported in this article.[Figure not available: see fulltext.]
- Samadi, Saadi,Ashouri, Akram,Majidian, Shiva,I Rashid, Hersh
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- Chemical Proteomics and Phenotypic Profiling Identifies the Aryl Hydrocarbon Receptor as a Molecular Target of the Utrophin Modulator Ezutromid
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Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease arising from mutations in the dystrophin gene. Upregulation of utrophin to compensate for the missing dystrophin offers a potential therapy independent of patient genotype. The first-in-class utrophin modulator ezutromid/SMT C1100 was developed from a phenotypic screen through to a Phase 2 clinical trial. Promising efficacy and evidence of target engagement was observed in DMD patients after 24 weeks of treatment, however trial endpoints were not met after 48 weeks. The objective of this study was to understand the mechanism of action of ezutromid which could explain the lack of sustained efficacy and help development of new generations of utrophin modulators. Using chemical proteomics and phenotypic profiling we show that the aryl hydrocarbon receptor (AhR) is a target of ezutromid. Several lines of evidence demonstrate that ezutromid binds AhR with an apparent KD of 50 nm and behaves as an AhR antagonist. Furthermore, other reported AhR antagonists also upregulate utrophin, showing that this pathway, which is currently being explored in other clinical applications including oncology and rheumatoid arthritis, could also be exploited in future DMD therapies.
- Wilkinson, Isabel V. L.,Perkins, Kelly J.,Dugdale, Hannah,Moir, Lee,Vuorinen, Aini,Chatzopoulou, Maria,Squire, Sarah E.,Monecke, Sebastian,Lomow, Alexander,Geese, Marcus,Charles, Philip D.,Burch, Peter,Tinsley, Jonathan M.,Wynne, Graham M.,Davies, Stephen G.,Wilson, Francis X.,Rastinejad, Fraydoon,Mohammed, Shabaz,Davies, Kay E.,Russell, Angela J.
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supporting information
p. 2420 - 2428
(2020/01/24)
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- Design and synthesis of Fmoc-SPPS-ready iodoarene amino acid pre-catalysts and their reactivity in the catalytic oxytosylation of ketones
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A small suite of iodo-aryl amide containing amino acids were synthesized and assessed as catalysts for the hypervalent iodine(III) mediated α-oxytosylation of ketones. The efficiency of each catalyst was determined by comparing the relative rates of catalysis in the direct α-oxytosylation of propiophenone. In addition, these catalysts can be easily converted to congeners that are suitable for Fmoc-solid phase peptide synthesis for facile incorporation into a chiral peptide framework. This work facilitates the broader goal of our program to develop peptide-based enantioselective catalysts for hypervalent iodine chemistry.
- Brummel, Beau R.,Giambalvo, Lauren N.,Gross, Kristopher G.,Kobra, Khadijatul,Lex, Timothy R.,McMillen, Colin D.,Panda, Soham,Pennington, William T.,Swasy, Maria I.,Whitehead, Daniel C.
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supporting information
(2020/02/22)
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- Rapid Organocatalytic Formation of Carbon Monoxide: Application towards Carbonylative Cross Couplings
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Herein, the first organocatalytic method for the transformation of non-derivatized formic acid into carbon monoxide (CO) is introduced. Formylpyrrolidine (FPyr) and trichlorotriazine (TCT), which is a cost-efficient commodity chemical, enable this decarbonylation. Utilization of dimethylformamide (DMF) as solvent and catalyst even allows for a rapid CO generation at room temperature. Application towards four different carbonylative cross coupling protocols demonstrates the high synthetic utility and versatility of the new approach. Remarkably, this also comprehends a carbonylative Sonogashira reaction at room temperature employing intrinsically difficult electron-deficient aryl iodides. Commercial 13C-enriched formic acid facilitates the production of radiolabeled compounds as exemplified by the pharmaceutical Moclobemide. Finally, comparative experiments verified that the present method is highly superior to other protocols for the activation of carboxylic acids.
- Zoller, Ben,Zapp, Josef,Huy, Peter H.
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supporting information
p. 9632 - 9638
(2020/07/13)
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- Divergent Synthesis of Tunable Cyclopentadienyl Ligands and Their Application in Rh-Catalyzed Enantioselective Synthesis of Isoindolinone
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A series of rhodium complexes bearing sterically and electronically tunable cyclopentadienyl ligands, prepared by utilizing Co2(CO)8-mediated [2+2+1] cyclization as a key step, were synthesized. In the presence of 2.5 mol% of CpmRh4, unprecedented enantioselective [4+1] annulation reaction of benzamides and alkenes was achieved with a broad substrate scope under mild reaction conditions, providing a variety of isoindolinones with excellent regio-and enantioselectivity (up to 94% yield, 97:3 er). Preliminary mechanistic studies suggest that the reaction involves an oxidative Heck reaction and an intramolecular enantioselective alkene hydroamination reaction.
- Cui, Wen-Jun,Wu, Zhi-Jie,Gu, Qing,You, Shu-Li
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supporting information
p. 7379 - 7385
(2020/08/19)
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- Optimizing the Benefit/Risk of Acetyl-CoA Carboxylase Inhibitors through Liver Targeting
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Preclinical and clinical data suggest that acetyl-CoA carboxylase (ACC) inhibitors have the potential to rebalance disordered lipid metabolism, leading to improvements in nonalcoholic steatohepatitis (NASH). Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein, we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a nonhuman primate model.
- Huard, Kim,Smith, Aaron C.,Cappon, Gregg,Dow, Robert L.,Edmonds, David J.,El-Kattan, Ayman,Esler, William P.,Fernando, Dilinie P.,Griffith, David A.,Kalgutkar, Amit S.,Ross, Trenton T.,Bagley, Scott W.,Beebe, David,Bi, Yi-An,Cabral, Shawn,Crowley, Collin,Doran, Shawn D.,Dowling, Matthew S.,Liras, Spiros,Mascitti, Vincent,Niosi, Mark,Pfefferkorn, Jeffrey A.,Polivkova, Jana,Préville, Cathy,Price, David A.,Shavnya, Andre,Shirai, Norimitsu,Smith, Andrew H.,Southers, James R.,Tess, David A.,Thuma, Benjamin A.,Varma, Manthena V.,Yang, Xiaojing
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p. 10879 - 10896
(2020/11/09)
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- Method for synthesizing alkenyl phosphate compounds
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The invention discloses a method for synthesizing alkenyl phosphate compounds with high selectivity. The method includes dissolving a gold catalyst, an alkyne shown as a formula II, and a phosphoric acid compound shown as a formula III into an organic solvent in a nitrogen atmosphere, stirring and reacting the mixture at 25-75 DEG C in a Schlenk reaction tube for 3-10 h, and subjecting an obtainedreaction solution to after-treatment to obtain an alkenyl phosphate compound shown as a formula Iv. The mole ratio of the gold catalyst, the alkyne shown as the formula II, and the phosphoric acid compound shown as the formula III is 0.01-0.05:1-2:1. In the method, the dual-function gold catalyst replaces present expensive ruthenium catalysts or high-toxicity mercury catalysts so that the methodhas advantages of high reaction stereoselectivity, low catalyst toxicity, low catalyst dosage, mild reaction condition, reduced energy consumption, a high yield, high substrate universality, simple and convenient operation, and the like.
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Paragraph 0026; 0027
(2019/11/21)
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- Method for synthesizing 1,5-benzodiazepine compound
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The invention discloses a method for synthesizing a 1,5-benzodiazepine compound. The method specifically comprises the following steps: dissolving a gold catalyst, an additive, alkyne of a formula IIshown in the specification, an o-phenylenediamine derivative of a formula III shown in the specification into an organic solvent, putting the solution into a pressure-resistant reaction tube, performing a stirring reaction for 6-24 hours at 25 DEG C so as to obtain a reaction liquid, and performing aftertreatment on the reaction liquid so as to obtain the 1,5-benzodiazepine compound of a formula IV shown in the specification, wherein the mass ratio of the gold catalyst of a formula I shown in the specification to the additive to the alkyne of the formula II shown in the specification to the o-phenylenediamine derivative of the formula III shown in the specification is (0.01-0.07):(0-0.1):(2.0-3.0):1. By adopting the method disclosed by the invention, a double-functional catalyst is used, the reaction can be performed under a room temperature condition, and thus energy consumption can be reduced; and the method has the advantages of being small in catalyst amount, high in yield, good insubstrate universality, simple and convenient in operation, and the like.
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Paragraph 0028
(2019/12/25)
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- Imidazole carbene ligand with amide remote basic functional group as well as synthesis method and application thereof
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The invention discloses an imidazole carbene ligand with an alkaline remote functional group, which is a compound shown as a formula (1). The ligand and gold can form a stable metal complex used for catalyzing cyclization reactions, rearrangement reactions, nucleophilic addition reactions and the like. The invention provides a synthetic route of the novel imidazole carbene ligand and a metal complex thereof, achieving simple and efficient alkyne nucleophilic addition. The NHC-Au catalyst is provided with a Lewis acid activation center taking gold as a center and an alkali activation center taking a basic group as a center, and a hindered Lewis acid-base pair can be formed by utilizing a unique linear structure of a monovalent gold complex (ligand-gold-substrate), so that beneficial interaction between the basic functional group and a nucleophilic reagent or substrate is realized, and dual synergistic activation effects of a catalytic system on a reaction transition state are achieved.
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Paragraph 0041-0044
(2019/12/02)
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- Pyrido[1,2-a][1,2,4]triazole carbene ligand as well as synthesis method and application thereof
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The invention provides a pyrido[1,2-a][1,2,4]triazole carbene ligand as well as a synthesis method and application thereof. A pyrido[1,2-a][1,2,4]triazole carbene-gold complex formed from the pyrido[1,2-a] [1,2,4]triazole carbene ligand shown as a formula V and gold can be applied to alkyne catalytic addition reaction, has Lewis acid/alkali double activation centers, and can depend on the 'synergistic activation effect' of the double activation centers, so that the catalytic effect which cannot be achieved or cannot be achieved by a conventional ligand is achieved, and the addition reaction ofa nucleophilic reagent to multiple bonds can be greatly accelerated.
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Paragraph 0037; 0041
(2019/12/02)
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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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- Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties
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Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.
- Hansen, Anders H?jgaard,Sergeev, Eugenia,Bolognini, Daniele,Sprenger, Richard R.,Ekberg, Jeppe Hvidtfeldt,Ejsing, Christer S.,McKenzie, Christine J.,Rexen Ulven, Elisabeth,Milligan, Graeme,Ulven, Trond
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supporting information
p. 9534 - 9550
(2018/10/24)
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- Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors
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FGF receptors (FGFRs) are tyrosine kinases that are overexpressed in diverse tumors by genetic alterations such as gene amplifications, somatic mutations and translocations. Owing to this characteristic, FGFRs are attractive targets for cancer treatment. It has been demonstrated that most multi-targeted, ATP competitive tyrosine kinase inhibitors are active against FGFRs as well as other kinases. The design of new and more selective inhibitors of FGFRs, which might be reduced off-target and side effects, is a difficult yet significant challenge. The results of the current investigation, show that novel Ponatinib analogues are highly active as FGFR inhibitors and that they possess reduced kinase insert domain receptor (KDR) activities. Observations made in a structure and activity relationship (SAR) investigation led to the development of a promising, orally available lead compound 4, which displays a 50–100 fold in vitro selectivity for inhibition of FGFR1-3 over KDR. In addition, biological evaluation of compound 4 showed that it displays significant antitumor activities in FGFR1-amplificated H1581 and FGFR2-amplificated SNU-16 xenograft models.
- Liu, Yang,Peng, Xia,Guan, Xiaocong,Lu, Dong,Xi, Yong,Jin, Shiyu,Chen, Hui,Zeng, Limin,Ai, Jing,Geng, Meiyu,Hu, Youhong
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p. 122 - 132
(2016/10/25)
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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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- Supramolecular bidentate phosphine ligand scaffolds from deconstructed Hamilton receptors
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There is constant demand for new ligand archictectures on which inorganic and organometallic structures can be leveraged. An important, but often synthetically challenging, class of ligands is bidentate phosphines. Here we report self-assembling, supramolecular bidentate ligand scaffolds based on deconstructed Hamilton receptors with binding affinities up to 800 ± 100 M-1
- Seidenkranz, Daniel T.,McGrath, Jacqueline M.,Zakharov, Lev N.,Pluth, Michael D.
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supporting information
p. 561 - 564
(2017/01/13)
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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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- Difluoromethylation of carboxylic acids via the addition of difluorinated phosphorus ylide to acyl chlorides
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A one-step protocol for the difluoromethylation of carboxylic acids is described. The reaction involves the interaction of intermediate acyl chlorides with in situ generated difluorinated phosphorus ylide Ph3P=CF2. Aromatic acids can be selectively transformed within one step either to bis-difluoromethylated alcohols or to difluorinated ketones depending on the particular reaction conditions. For bulky α-branched carboxylic acids, only ketones are produced.
- Trifonov, Alexey L.,Levin, Vitalij V.,Struchkova, Marina I.,Dilman, Alexander D.
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supporting information
p. 5304 - 5307
(2017/11/06)
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- From Lead to Drug Candidate: Optimization of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as Agents for the Treatment of Triple Negative Breast Cancer
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Herein we report the sophisticated process of structural optimization toward a previously disclosed Src inhibitor, compound 1, which showed high potency in the treatment of triple negative breast cancer (TNBC) both in vitro and in vivo but had considerable toxicity. A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were synthesized. In vitro cell-based phenotypic screening together with in vivo assays and structure-activity relationship (SAR) studies finally led to the discovery of N-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (13an). 13an is a multikinase inhibitor, which potently inhibited Src (IC50 = 0.003 μM), KDR (IC50 = 0.032 μM), and several kinases involved in the MAPK signal transduction. This compound showed potent anti-TNBC activities both in vitro and in vivo, and good pharmacokinetic properties and low toxicity. Mechanisms of action of anti-TNBC were also investigated. Collectively, the data obtained in this study indicate that 13an could be a promising drug candidate for the treatment of TNBC and hence merits further studies.
- Zhang, Chun-Hui,Chen, Kai,Jiao, Yan,Li, Lin-Li,Li, Ya-Ping,Zhang, Rong-Jie,Zheng, Ming-Wu,Zhong, Lei,Huang, Shen-Zhen,Song, Chun-Li,Lin, Wan-Ting,Yang, Jiao,Xiang, Rong,Peng, Bing,Han, Jun-Hong,Lu, Guang-Wen,Wei, Yu-Quan,Yang, Sheng-Yong
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supporting information
p. 9788 - 9805
(2016/11/19)
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- A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles
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Synthetic macrocycles are an attractive area in drug discovery. However, their use has been hindered by a lack of versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries. Herein, we describe a new concept in library synthesis, termed multidimensional diversity-oriented synthesis, and its application towards macrocycles. This enabled the step-efficient generation of a library of 45 novel, structurally diverse, and highly-functionalized macrocycles based around a broad range of scaffolds and incorporating a wide variety of biologically relevant structural motifs. The synthesis strategy exploited the diverse reactivity of aza-ylides and imines, and featured eight different macrocyclization methods, two of which were novel. Computational analyses reveal a broad coverage of molecular shape space by the library and provides insight into how the various diversity-generating steps of the synthesis strategy impact on molecular shape.
- Nie, Feilin,Kunciw, Dominique L.,Wilcke, David,Stokes, Jamie E.,Galloway, Warren R. J. D.,Bartlett, Sean,Sore, Hannah F.,Spring, David R.
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supporting information
p. 11139 - 11143
(2016/10/13)
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- NOVEL COMPOUNDS AS HISTONE DEACETYLASE 6 INHIBITORS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME
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The present invention relates to novel compounds having histone deacetylase 6 (HDAC6) inhibitory activity, isomers thereof, or pharmaceutically acceptable salts thereof, the use thereof for the preparation of therapeutic medicaments, pharmaceutical compositions comprising the same, a method of treating disease using the composition, and methods for preparing the novel compounds. The novel compounds according to the present invention have histone deacetylase 6 (HDAC6) inhibitory activity, and are effective for the prevention or treatment of HDAC6-associated diseases, including cancer, inflammatory diseases, autoimmune diseases, neurological diseases and neurodegenerative disorders.
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Paragraph 983; 984
(2015/10/05)
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- P2X4 RECEPTOR MODULATING COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein are P2X4 receptor modulating compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, including but not limited to, chronic pain, neuropathy, inflammatory diseases and central nervous system disorders.
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Paragraph 00210
(2015/06/25)
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- P2X4 RECEPTOR MODULATING COMPOUNDS
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Provided herein are P2X4 receptor modulating compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, including but not limited to, chronic pain, neuropathy, inflammatory diseases and central nervous system disorders.
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Paragraph 00235
(2015/06/25)
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- Relative Rate Profiles of Functionalized Iodoarene Catalysts for Iodine(III) Oxidations
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A series of rate studies were conducted to evaluate the steric and electronic properties that govern the reactivity of iodoarene amide catalysts in the α-oxytosylation of propiophenone. A meta-substituted benzamide catalyst emerged as the most reactive. This catalyst was employed in the α-oxytosylation of a series of substituted propiophenones, returning the α-tosyloxy ketone products in excellent isolated yield.
- Lex, Timothy R.,Swasy, Maria I.,Whitehead, Daniel C.
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p. 12234 - 12243
(2016/01/09)
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- Rhodium-catalyzed C-H alkynylation of arenes at room temperature
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The rhodium(III)-catalyzed ortho C-H alkynylation of non-electronically activated arenes is disclosed. This process features a straightforward and highly effective protocol for the synthesis of functionalized alkynes and represents the first example of merging a hypervalent iodine reagent with rhodium(III) catalysis. Notably, this reaction proceeds at room temperature, tolerates a variety of functional groups, and more importantly, exhibits high selectivity for monoalkynylation. Hot rhod: A rhodium-catalyzed, electronically reversed Sonogashira reaction between unbiased arenes and the hypervalent iodine reagent 1 proceeds through C-H activation. This reaction displays excellent functional-group tolerance and high efficiency, and thus opens a new synthetic pathway to access functionalized alkynes. Cp=C5Me5, DCE=1,2-dichloroethane, Piv=pivaloyl, TIPS=triisopropylsilyl.
- Feng, Chao,Loh, Teck-Peng
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supporting information
p. 2722 - 2726
(2014/03/21)
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- De-novo designed library of benzoylureas as inhibitors of BCL-X L: Synthesis, structural and biochemical characterization
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The prosurvival BCL-2 proteins are attractive yet challenging targets for medicinal chemists. Their involvement in the initiation and progression of many, if not all, tumors makes them prime targets for developing new anticancer therapies. We present our approach based on de novo structure-based drug design. Using known structural information from complexes engaging opposing members of the BCL-2 family of proteins, we designed peptidomimetic compounds using a benzoylurea scaffold to reproduce key interactions between these proteins. A library stemming from the initial de novo designed scaffold led to the discovery of ligands with low micromolar potency (KD = 4 μM) and selectivity for BCL-XL. These compounds bind in the canonical BH3 binding groove in a binding mode distinct from previously known BCL-2 inhibitors. The results of our study provide insight into the design of a new class of antagonists targeting a challenging class of protein-protein interactions.
- Brady, Ryan M.,Vom, Amelia,Roy, Michael J.,Toovey, Nathan,Smith, Brian J.,Moss, Rebecca M.,Hatzis, Effie,Huang, David C. S.,Parisot, John P.,Yang, Hong,Street, Ian P.,Colman, Peter M.,Czabotar, Peter E.,Baell, Jonathan B.,Lessene, Guillaume
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p. 1323 - 1343
(2014/03/21)
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- Identification of novel SIRT2-selective inhibitors using a click chemistry approach
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A series of 114 SIRT inhibitor candidates was assembled using 'click chemistry', by reacting two alkynes bearing 2-anilinobenzamide pharmacophore with 57 azide building blocks in the presence of Cu(I) catalyst. Screening identified two SIRT2-selective inhibitors, which were more SIRT2-selective than AGK2, a known SIRT2 inhibitor. These findings will be useful for further development of SIRT2-selective inhibitors.
- Tatum, Prima R.,Sawada, Hideyuki,Ota, Yosuke,Itoh, Yukihiro,Zhan, Peng,Ieda, Naoya,Nakagawa, Hidehiko,Miyata, Naoki,Suzuki, Takayoshi
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p. 1871 - 1874
(2014/04/17)
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- Mild rhodium(III)-catalyzed C-H allylation with 4-vinyl-1,3-dioxolan-2-ones: Direct and stereoselective synthesis of (E)-allylic alcohols
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A rhodium(III)-catalyzed C-H direct allylation reaction with 4-vinyl-1,3-dioxolan-2-ones has been developed. The reaction provides a facile and stereoselective access to substituted-(E)-allylic alcohols under mild and redox-neutral reaction conditions. Olefinic C-H activation is applicable, giving multifunctionalized skipped dienes in good yields. Minimal double-bond migration was observed.
- Zhang, Shang-Shi,Wu, Jia-Qiang,Lao, Ye-Xing,Liu, Xu-Ge,Liu, Yao,Lv, Wen-Xin,Tan, Dong-Hang,Zeng, Yao-Fu,Wang, Honggen
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supporting information
p. 6412 - 6415
(2015/01/09)
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- Copper-catalyzed phosphorylation of sp2 C-H bonds
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The phosphorylation of the ortho C-H bonds in benzamides containing an 8-aminoquinoline moiety as a bidentate directing group with H-phosphonates using copper as a catalyst under mild temperature conditions is described. This method shows high functional group compatibility and selectively gives mono-substituted products. This journal is
- Wang, Shan,Guo, Rui,Wang, Gao,Chen, Shan-Yong,Yu, Xiao-Qi
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supporting information
p. 12718 - 12721
(2015/05/20)
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- Synthesis and biological evaluation of triazole-containing N-acyl homoserine lactones as quorum sensing modulators
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Many bacterial species are capable of assessing their local population densities through a cell-cell signaling mechanism termed quorum sensing (QS). This intercellular communication process is mediated by small molecule or peptide ligands and their cognate protein receptors. Numerous pathogens use QS to initiate virulence once they achieve a threshold cell number on a host. Consequently, approaches to intercept QS have attracted considerable attention as potential anti-infective therapies. Our interest in the development of small molecule tools to modulate QS pathways motivated us to evaluate triazole-containing analogs of natural N-acyl l-homoserine lactone (AHL) signals as non-native QS agonists and antagonists in Gram-negative bacteria. We synthesized 72 triazole derivatives of five broad structure types in high yields and purities using efficient Cu(i)-catalyzed azide-alkyne couplings. These compounds were evaluated for their ability to activate or inhibit two QS receptors from two prevalent pathogens-LasR from Pseudomonas aeruginosa and AbaR from Acinetobacter baumannii-using bacterial reporter strains. Several triazole derivatives were identified that were capable of strongly modulating the activity of LasR and AbaR. These compounds represent a new and synthetically accessible class of AHL analogs, and could find utility as chemical tools to study QS and its role in bacterial virulence.
- Stacy, Danielle M.,Le Quement, Sebastian T.,Hansen, Casper L.,Clausen, Janie W.,Tolker-Nielsen, Tim,Brummond, Jacob W.,Givskov, Michael,Nielsen, Thomas E.,Blackwell, Helen E.
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supporting information
p. 938 - 954
(2013/02/26)
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- Nickel-catalyzed direct alkylation of C-H bonds in benzamides and acrylamides with functionalized alkyl halides via bidentate-chelation assistance
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The alkylation of the ortho C-H bonds in benzamides and acrylamides containing an 8-aminoquinoline moiety as a bidentate directing group with unactivated alkyl halides using nickel complexes as catalysts is described. The reaction shows high functional group compatibility. In reactions of meta-substituted aromatic amides, the reaction proceeds in a highly selective manner at the less hindered C-H bond.
- Aihara, Yoshinori,Chatani, Naoto
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supporting information
p. 5308 - 5311
(2013/05/21)
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- Rh[III]-catalyzed direct C-H amination using N -chloroamines at room temperature
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An efficient Rh(III)-catalyzed direct C-H amination of N-pivaloyloxy benzamides with N-chloroamines proceeding at room temperature was achieved. The versatile directing group allows for selective mono- and diamination and can be readily converted to give valuable benzamide or aminoaniline derivatives. Mechanistic studies have been carried out to elucidate the reaction pathway.
- Grohmann, Christoph,Wang, Honggen,Glorius, Frank
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supporting information; experimental part
p. 656 - 659
(2012/03/08)
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- Avicholic acid: A lead compound from birds on the route to potent TGR5 modulators
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Grounding on our former 3D QSAR studies, a knowledge-based screen of natural bile acids from diverse animal species has led to the identification of avicholic acid as a selective but weak TGR5 agonist. Chemical modifications of this compound resulted in the disclosure of 6α-ethyl-16-epi-avicholic acid that shows enhanced potency at TGR5 and FXR receptors. The synthesis, biological appraisals, and structure-activity relationships of this series of compounds are herein described. Moreover, a thorough physicochemical characterization of 6α-ethyl-16-epi-avicholic acid as compared to naturally occurring bile acids is reported and discussed.
- Pellicciari, Roberto,Gioiello, Antimo,Sabbatini, Paola,Venturoni, Francesco,Nuti, Roberto,Colliva, Carolina,Rizzo, Giovanni,Adorini, Luciano,Pruzanski, Mark,Roda, Aldo,MacChiarulo, Antonio
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supporting information; experimental part
p. 273 - 277
(2012/06/01)
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- Mild rhodium(III)-catalyzed C-H activation and intermolecular annulation with allenes
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All(enes) great! A novel RhIII-catalyzed oxidative coupling with allenes under mild conditions provides heterocycles with exocyclic double bonds. This reaction features low catalyst loadings, high regio- and stereoselectivity, and excellent substrate scope. The products were derivatized and preliminary mechanistic studies were conducted. Copyright
- Wang, Honggen,Glorius, Frank
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supporting information; experimental part
p. 7318 - 7322
(2012/09/08)
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- NOVEL TETRADENTATE PLATINUM COMPLEXES
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Novel phosphorescent tetradentate platinum (II) compounds comprising a twisted aryl group are provided. Also provided are novel phosphorescent tetradentate platinum (II) compounds comprising an imidazo[1,2-f]phenanthridine moiety. The compounds may be used in organic light emitting devices to provide improved device efficiency, line shape and lifetime.
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Page/Page column 122-123
(2012/09/11)
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- Fluorescent β-cyclodextrins modified by isomeric aminobenzamides: Synthesis, conformational analysis, and fluorescent behaviors
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Three isomeric fluorescent β-cyclodextrins bearing 2-, 3-, and 4-(2-aminoethyl)amino-N-butylbenzamide, respectively (1-3) have been synthesized. The conformations of these fluorescent CDs have been investigated by 2D NMR and induced circular dichromism. It is confirmed that the ortho isomer 1 takes a butyl-included conformation, while the other two isomers 2 and 3 display a phenyl-included conformation, respectively. The three fluorescent CDs 1-3 exhibited totally different self- and guest-inclusion fluorescence behavior. In the presence of adamantane carboxylate sodium (ADA) or deoxycholate sodium (DCA), the fluorescence intensity of 1 showed an enhancement over 1-fold, while 2 exhibited dramatic fluorescence quenching. Interestingly, the fluorescent responses of 3 toward two guests respectively were highly distinguishable. The fluorescence intensity of 3 only showed a slight increase upon the addition of ADA, but the addition of DCA led to a large decrease in fluorescence intensity. The investigations have been further carried out by 2D NMR, induced circular dichromism, fluorescence spectroscopy and molecular modeling to explore the relationships between the conformations and the fluorescence characteristics of CDs 1-3 in the absence and presence of guest molecules. On the basis of the above investigations, the origins for the different fluorescence behaviors have been proposed.
- Wang, Lei,Zhong, Cheng,Xue, Peng,Fu, Enqin
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experimental part
p. 4874 - 4883
(2011/08/04)
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- PYRROLIDINE SUBSTITUTED FLAVONES FOR THE TREATMENT OF INFLAMMATORY DISORDERS
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The present invention relates to the use of a compound of formula 1, a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, for the treatment of an inflammatory disorder. The invention further relates to a pharmaceutical composition comprising a compound of formula 1 and at least one pharmaceutically acceptable carrier, for use in the treatment of an inflammatory disorder. The invention also relates to a method for the treatment of an inflammatory disorder by administering a therapeutically effective amount of the compound of formula 1 to a subject in need thereof.
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Page/Page column 46-47
(2011/09/30)
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- TGR5 MODULATORS AND METHODS OF USE THEREOF
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The invention relates to compounds of Formula (A): (A) or a salt, solvate, hydrate, or amino acid conjugate thereof. The compounds of formula A are TGR5 modulators useful for the prevention and treatment of disease.
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Page/Page column 24-26
(2010/07/10)
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- Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold
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Investigations into the structure-activity relationships (SAR) of a series of phthalazine-based inhibitors of p38 are described. These efforts originated from quinazoline 1 and through rational design led to the development of a series of orally bioavailable, potent, and selective inhibitors. Kinase selectivity was achieved by exploiting a collection of interactions with p38a including close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a residue flip with Gy110. Substitutions on the phthalazine influenced the pharmacokinetic properties, of which compound 16 displayed the most desirable profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave a >50% decrease in TNFα production.
- Herberich, Brad,Cao, Guo-Qiang,Chakrabarti, Partha P.,Falsey, James R.,Pettus, Liping,Rzasa, Robert M.,Reed, Anthony B.,Reichelt, Andreas,Sham, Kelvin,Thaman, Maya,Wurz, Ryan P.,Xu, Shimin,Zhang, Dawei,Hsieh, Faye,Lee, Matthew R.,Syed, Rashid,Li, Vivian,Grosfeld, David,Plant, Matthew H.,Henkle, Bradley,Sherman, Lisa,Middleton, Scot,Lu, Min Wong,Tasker, Andrew S.
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experimental part
p. 6271 - 6279
(2009/10/17)
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- Alkynylpyrimidine amide derivatives as potent, selective, and orally active inhibitors of Tie-2 kinase
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The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-F c conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.
- Cee, Victor J.,Albrecht, Brian K.,Geuns-Meyer, Stephanie,Hughes, Paul,Bellon, Steve,Bready, James,Caenepeel, Sean,Chaffee, Stuart C.,Coxon, Angela,Emery, Maurice,Fretland, Jenne,Gallant, Paul,Gu, Yan,Hodous, Brian L.,Hoffman, Doug,Johnson, Rebecca E.,Kendall, Richard,Kim, Joseph L.,Long, Alexander M.,McGowan, David,Morrison, Michael,Olivieri, Philip R.,Patel, Vinod F.,Polverino, Anthony,Powers, David,Rose, Paul,Wang, Ling,Zhao, Huilin
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p. 627 - 640
(2007/10/03)
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- De novo parallel design, synthesis and evaluation of inhibitors against the reverse transcriptase of human immunodeficiency virus type-1 and drug-resistant variants
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We used molecular modeling to design de novo broad-range inhibitors against wild type and drug-resistant variants of the reverse transcriptase (RT) of human immunodeficiency virus type-1 (HIV-1). First, we screened for small fragments that would interact with each one of four RT structures (one wild type and three mutants). Then, these fragments were linked to build a scaffold molecule. Out of 27 different compounds that were synthesized, four inhibited the DNA polymerase activity of RT with IC50 values below 10 μM. Compound 5f inhibited RT with an IC50 value of about 3.5 μM, while inhibiting drug-resistant RT variants more efficiently than the clinically used drug, nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b: 2′,3′-e-]-[1,4]diazepin-6-one). 5f also inhibited the RT ribonuclease H activity with an IC50 of 20 μM and therefore, unlike nevirapine, targets both RT activities. Accordingly, 5f can serve as lead for developing novel inhibitors against RT that may be used to suppress HIV-1 growth.
- Herschhorn, Alon,Lerman, Lena,Weitman, Michal,Gleenberg, Iris Oz,Nudelman, Abraham,Hizi, Amnon
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p. 2370 - 2384
(2008/02/07)
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- Ring B functionalization of scalarane sesterterpenes by radical relay halogenation
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The functionalization of the B-ring of the scalarane framework has been achieved for the first time by a radical relay halogenation (RRH) synthetic method. The known scalaranic methyl ester, which was prepared by a procedure with an overall yield higher than those reported in the literature, has been used as the starting substrate. Some theoretical considerations explaining the course of RRH reaction are also presented.
- Kulci?ki, Veaceslav,Ungur, Nicon,Gavagnin, Margherita,Castelluccio, Francesco,Cimino, Guido
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p. 7617 - 7623
(2008/02/08)
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- First chemical synthesis, aggregation behavior and cholesterol solubilization properties of pythocholic acid and 16α-hydroxycholic acid
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The first chemical synthesis of pythocholic acid, a major component of python's bile, and 3α,7α,12α,16α-tetrahydroxy-5β- cholan-24-oic acid (16α-hydroxycholic acid), a minor component in Shoebill stork's bile, was achieved starting from readily available cholic acid in overall yields of 5% and 5.5%, respectively, through a common intermediate. A biomimetic template-directed remote functionalization strategy was utilized to selectively functionalize C-16 of the steroid skeleton. This synthesis involves a series of regio and chemoselective transformations. Pythocholic acid showed unusually low critical micellar concentration (CMC) with high cholesterol solubilization ability. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Nonappa,Maitra, Uday
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p. 3331 - 3336
(2008/02/10)
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- Nonsteroidal benzophenone-containing analogues of cholesterol
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The four benzophenones, 10-13, containing the natural side chain of cholesterol (1) have been synthesized to explore whether the tetracyclic nucleus of 1 is essential for its biochemical properties. The syntheses of analogues 10, 11, and 13 feature efficient introduction of the alkyl side chain by Suzuki coupling. Preliminary biochemical evaluation of 10 and 12 suggests that the sterol tetracyclic nucleus is not required for biological compatibility with 1.
- Gan, Yonghong,Blank, David H.,Ney, Joshua E.,Spencer, Thomas A.
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p. 5864 - 5869
(2007/10/03)
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