- Harnessing the Role of HDAC6 in Idiopathic Pulmonary Fibrosis: Design, Synthesis, Structural Analysis, and Biological Evaluation of Potent Inhibitors
-
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive-fibrosing phenotype. IPF has been associated with aberrant HDAC activities confirmed by our immunohistochemistry studies on HDAC6 overexpression in IPF lung tissues. We herein developed a series of novelhHDAC6 inhibitors, having low inhibitory potency overhHDAC1 andhHDAC8, as potential pharmacological tools for IPF treatment. Their inhibitory potency was combined with lowin vitroandin vivotoxicity. Structural analysis of 6h and structure-activity relationship studies contributed to the optimization of the binding mode of the new molecules. The best-performing analogues were tested for their efficacy in inhibiting fibrotic sphere formation and cell viability, proving their capability in reverting the IPF phenotype. The efficacy of analogue 6h was also determined in a validated human lung model of TGF-β1-dependent fibrogenesis. The results highlighted in this manuscript may pave the way for the identification of first-in-class molecules for the treatment of IPF.
- Campiani, Giuseppe,Cavella, Caterina,Osko, Jeremy D.,Brindisi, Margherita,Relitti, Nicola,Brogi, Simone,Saraswati, A. Prasanth,Federico, Stefano,Chemi, Giulia,Maramai, Samuele,Carullo, Gabriele,Jaeger, Benedikt,Carleo, Alfonso,Benedetti, Rosaria,Sarno, Federica,Lamponi, Stefania,Rottoli, Paola,Bargagli, Elena,Bertucci, Carlo,Tedesco, Daniele,Herp, Daniel,Senger, Johanna,Ruberti, Giovina,Saccoccia, Fulvio,Saponara, Simona,Gorelli, Beatrice,Valoti, Massimo,Kennedy, Breándan,Sundaramurthi, Husvinee,Butini, Stefania,Jung, Manfred,Roach, Katy M.,Altucci, Lucia,Bradding, Peter,Christianson, David W.,Gemma, Sandra,Prasse, Antje
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p. 9960 - 9988
(2021/07/31)
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- Ag(I)-Catalyzed C-H Carboxylation of Thiophene Derivatives
-
CO2utilization is an attractive aspect as it allows the direct conversion of CO2into valuable chemicals. In this regard, direct incorporation of CO2into the C-H bond of heteroaromatic compounds is important due to the ubiquitous structural motifs of the heteroaromatic carboxylic acids. Herein, we report the Ag-catalyzed C-H carboxylation of thiophene derivatives. This new catalytic system involving a phosphine ligand and lithiumtert-butoxide enables the direct carboxylation of thiophenes under mild reaction conditions. Experimental studies revealed that the use oftert-butyl alkoxide is critical for the exergonic formation of an arylsilver intermediate, and the results were further supported by density functional theory calculations.
- Lee, Mijung,Hwang, Young Kyu,Kwak, Jaesung
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p. 3136 - 3144
(2021/09/30)
-
- A Suzuki Approach to Quinone-Based Diarylethene Photochromes
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Diarylethene photochromes show promise for use in advanced organic electronic and photonic materials with burgeoning considerations for biological applications; however, these compounds typically require UV light for photoswitching in at least one direction, thus limiting their appeal. We here introduce a naphthoquinone-based diarylethene that switches between open and closed forms with visible light. The synthesis of this quinone diarylethene relies on Suzuki methodology, allowing for the inclusion of functional groups not otherwise accessible with current synthetic routes.
- Carter, Dorothy A.,Mitchell, Travis B.,Myers, Shea D.,Novak, Frank A.,Patel, Dinesh G.
-
-
- BORON CONTAINING COMPOUNDS AND THEIR USES
-
The present disclosure contemplates a boron-containing compound, a composition containing a pesticidal effective amount of that compound dissolved or dispersed in a carrier medium, and a method of reducing, ameliorating, or controlling an infestation by a pest, particularly a fungus, by administering a contemplated composition to a plant or animal in need.
- -
-
Paragraph 0219-0220
(2021/01/23)
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- Visible Light-Promoted Photocatalytic C-5 Carboxylation of 8-Aminoquinoline Amides and Sulfonamides via a Single Electron Transfer Pathway
-
An efficient photocatalytic method was developed for the remote C5-H bond carboxylation of 8-aminoquinoline amide and sulfonamide derivatives. This methodology uses in situ generated ?CBr3 radical as a carboxylation agent with alcohol and is further extended to a variety of arenes and heteroarenes to synthesize the desired carboxylated product in moderate-to-good yields. The reaction proceeding through a single electron transfer pathway was established by a control experiment, and a butylated hydroxytoluene-trapped aryl radical cation intermediate in high-resolution mass spectrometry was identified.
- Sen, Chiranjit,Sahoo, Tapan,Singh, Harshvardhan,Suresh, Eringathodi,Ghosh, Subhash Chandra
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p. 9869 - 9896
(2019/08/20)
-
- A biocatalytic method for the chemoselective aerobic oxidation of aldehydes to carboxylic acids
-
Herein, we present a study on the oxidation of aldehydes to carboxylic acids using three recombinant aldehyde dehydrogenases (ALDHs). The ALDHs were used in purified form with a nicotinamide oxidase (NOx), which recycles the catalytic NAD+ at the expense of dioxygen (air at atmospheric pressure). The reaction was studied also with lyophilised whole cell as well as resting cell biocatalysts for more convenient practical application. The optimised biocatalytic oxidation runs in phosphate buffer at pH 8.5 and at 40 °C. From a set of sixty-one aliphatic, aryl-Aliphatic, benzylic, hetero-Aromatic and bicyclic aldehydes, fifty were converted with elevated yield (up to >99%). The exceptions were a few ortho-substituted benzaldehydes, bicyclic heteroaromatic aldehydes and 2-phenylpropanal. In all cases, the expected carboxylic acid was shown to be the only product (>99% chemoselectivity). Other oxidisable functionalities within the same molecule (e.g. hydroxyl, alkene, and heteroaromatic nitrogen or sulphur atoms) remained untouched. The reaction was scaled for the oxidation of 5-(hydroxymethyl)furfural (2 g), a bio-based starting material, to afford 5-(hydroxymethyl)furoic acid in 61% isolated yield. The new biocatalytic method avoids the use of toxic or unsafe oxidants, strong acids or bases, or undesired solvents. It shows applicability across a wide range of substrates, and retains perfect chemoselectivity. Alternative oxidisable groups were not converted, and other classical side-reactions (e.g. halogenation of unsaturated functionalities, Dakin-Type oxidation) did not occur. In comparison to other established enzymatic methods such as the use of oxidases (where the concomitant oxidation of alcohols and aldehydes is common), ALDHs offer greatly improved selectivity.
- Knaus, Tanja,Tseliou, Vasilis,Humphreys, Luke D.,Scrutton, Nigel S.,Mutti, Francesco G.
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supporting information
p. 3931 - 3943
(2018/09/11)
-
- Discovery of thiophene-containing biaryl amide derivatives as novel glucagon receptor antagonists
-
A novel series of thiophene-containing biaryl amide glucagon receptor (GCGR) antagonists were designed and synthesized. Two compounds of this series, 14f and 14h, exhibited good GCGR binding (IC50?=?6.1 and 4.4?μm, respectively) and cAMP functional activities (IC50?=?4.4 and 14.4?μm, respectively). The possible binding modes of compounds 14f and 14h with GCGR were explored by molecular simulation.
- Li, Jia,Feng, Yang,Li, Huihui,Shu, Shuangjie,Dai, Antao,Cai, Xiaoqing,Wang, Jiang,Yang, Dehua,Ma, Dakota,Wang, Ming-Wei,Liu, Hong
-
p. 1241 - 1254
(2018/04/12)
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- COMPOUNDS FOR THE TREATMENT OF MEDICAL DISORDERS
-
Compounds, methods of use, and processes for making inhibitors of complement Factor D comprising Formula (I), or a pharmaceutically acceptable salt or composition thereof The inhibitors described herein target Factor D and inhibit or regulate the complement cascade. The inhibitors of Factor D described herein reduce the excessive activation of complement.
- -
-
Paragraph 0510
(2017/03/14)
-
- AMIDE COMPOUNDS FOR TREATMENT OF MEDICAL DISORDERS
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Compounds, methods of use, and processes for making inhibitors of complement Factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof wherein R12 or R13 on the A group is an amide substituent (R32) are provided. The inhibitors described herein target Factor D and inhibit or regulate the complement cascade. The inhibitors of Factor D described herein are capable of reducing the excessive activation of complement.
- -
-
Paragraph 0587
(2017/03/14)
-
- Development of a practical and scalable route for the preparation of the deacetoxytubuvaline (dTuv) fragment of pretubulysin and analogs
-
We present herein a novel and convenient route for the scaling-up of the dTuv fragment of pretubulysin. The newly conceived chemical path involves a practical and efficient one-step procedure for the preparation of a key thiazole intermediate, followed by high-yielding Wittig olefination/reduction steps. The optimized route, starting from the inexpensive and non-toxic l-cysteine, encompasses five synthetic steps and only two chromatographic purifications, thus displaying a dramatically increased overall yield. The versatility of the proposed approach also provides new hints for the exploration of pretubulysin derivatives bearing diverse heterocyclic portions.
- Brindisi, Margherita,Maramai, Samuele,Grillo, Alessandro,Brogi, Simone,Butini, Stefania,Novellino, Ettore,Campiani, Giuseppe,Gemma, Sandra
-
supporting information
p. 920 - 923
(2016/02/05)
-
- Effect of π-spacers and anchoring groups on the photovoltaic performances of ullazine-based dyes
-
Three ullazine-based organic sensitizers (QD1, QD2 and QD3) have been designed, synthesized, and characterized for dye-sensitized solar cells (DSSCs). Ullazine possesses some attractive properties, such as a planar π-system to promote intensely the intram
- Qiao, He,Deng, Yanghua,Peng, Ruipeng,Wang, Guo,Yuan, Jing,Tan, Songting
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p. 70046 - 70055
(2016/08/06)
-
- Functionalization of photochromic dithienylmaleimides
-
Photochromic dithienylmaleimides are well known molecular switches, but for applications the suitable functionalization of the photochromic scaffold is required. We report here synthetic routes to dithienylmaleimides, which are functionalized at three different positions: at each of the thiophene moieties and the maleimide nitrogen. A Perkin-type condensation of two thiophene precursors is used as the key step to assemble the maleimide core, which allows the synthesis of non-symmetrically substituted dithienylmaleimides, such as photochromic amino acids. A different approach to the maleimide core is provided by the reaction of a dithienylmaleic anhydride with amines or hydrazides leading to maleimide protected dithienylmaleimides and photochromic labeled natural amino acids. The photochromic properties of the new photoswitches were investigated showing reversible photochromism in polar organic solvents. This journal is
- Wutz,Falenczyk,Kuzmanovic,K?nig
-
p. 18075 - 18086
(2015/03/04)
-
- Catalyst-controlled regiodivergent C-H borylation of multifunctionalized heteroarenes by using iridium complexes
-
The regiodivergent C-H borylation of 2,5-disubstituted heteroarenes with bis(pinacolato)diboron was achieved by using iridium catalysts formed in situ from [Ir(OMe)(cod)]2/dtbpy (cod=1,5-cyclooctadiene, dtbpy: 4,4′-di-tert-butyl-2,2′-bipyridine) or [Ir(OMe)(cod)]2/2 AsPh3. When [Ir(OMe)(cod)]2/dtbpy was used as the catalyst, borylation at the 4-position proceeded selectively to afford 4-borylated products in high yields (dtbpy system A). The regioselectivity changed when the [Ir(OMe)(cod)]2/2 AsPh3 catalyst was used; 3-borylated products were obtained in high yields with high regioselectivity (AsPh3 system B). The regioselectivity of borylation was easily controlled by changing the ligands. This reaction was used in the syntheses of two different bioactive compound analogues by using the same starting material. Minor adjustments, major differences: The regiodivergent C-H borylation of 2,5-disubstituted heteroarenes with bis(pinacolato)diboron was achieved by using iridium catalysts formed in situ from [Ir(OMe)(cod)]2/dtbpy (cod=1,5-cyclooctadiene, dtbpy: 4,4'-di-tert-butyl-2,2'-bipyridine) or [Ir(OMe)(cod)]2/2 AsPh3 (see scheme).
- Sasaki, Ikuo,Taguchi, Jumpei,Hiraki, Shotaro,Ito, Hajime,Ishiyama, Tatsuo
-
supporting information
p. 9236 - 9241
(2015/06/16)
-
- SELECTIVE HDAC6 INHIBITORS
-
The present invention provides hydroxamic acids of the formula described herein, that have activity toward inhibiting histone deacetylases, and in particular HDAC6. Also contemplated are pharmaceutical compositions and methods of use of an effective amount of the hydroxamic acid compounds provided, for treating a disease in a subject. In certain embodiments, the subject is afflicted with cancer, neurodegenerative disease, or HIV infection.
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-
Page/Page column 47
(2015/07/15)
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- DMSO/I2 mediated C-C bond cleavage of α-ketoaldehydes followed by C-O bond formation: A metal-free approach for one-pot esterification
-
A novel and efficient I2/DMSO mediated metal-free strategy is presented for the direct C-C bond cleavage of aryl-/heteroaryl- or aliphatic α-ketoaldehydes by C2-decarbonylation and C1-carbonyl oxidation to give the corresponding carboxylic acids followed by esterification in one pot, offering excellent yields in both the steps. Here, DMSO acts as the oxygen source/oxidant and this reaction works very well under both conventional heating and microwave irradiation. This is a very simple and convenient protocol.
- Venkateswarlu, Vunnam,Aravinda Kumar,Gupta, Sorav,Singh, Deepika,Vishwakarma, Ram A.,Sawant, Sanghapal D.
-
p. 7973 - 7978
(2015/07/27)
-
- Visible-Light-Induced Direct Photocatalytic Carboxylation of Indoles with CBr4/MeOH
-
Photocatalysis enables the cascade reactions of indoles and CBr4 in MeOH through a C(sp2)-H functionalization/methanolysis sequence. The title reaction provides an efficient access to indole 2- and 3-carboxylates in a single operation (no preinstallation of protecting as well as directing groups was required) with good yields under mild reaction conditions. Shedding light on indole: The regioselective alkoxycarboxylation of indoles and heteroarenes using the CBr4/MeOH couple was accomplished through visible-light-induced photoredox catalysis. The described photocatalytic strategy features operational simplicity as well as high functional-group tolerance and represents a direct procedure to access indole carboxylates in generally moderate to good yields (see scheme).
- Yang, Qing-Qing,Marchini, Marianna,Xiao, Wen-Jing,Ceroni, Paola,Bandini, Marco
-
supporting information
p. 18052 - 18056
(2015/12/24)
-
- Discovery of (S)-1-(1-(Imidazo[1,2- a ]pyridin-6-yl)ethyl)-6-(1-methyl-1 H -pyrazol-4-yl)-1 H -[1,2,3]triazolo[4,5- b ]pyrazine (Volitinib) as a Highly Potent and Selective Mesenchymal-Epithelial Transition Factor (c-Met) Inhibitor in Clinical Development for Treatment of Cancer
-
HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure-activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.
- Jia, Hong,Dai, Guangxiu,Weng, Jianyang,Zhang, Zhulin,Wang, Qing,Zhou, Feng,Jiao, Longxian,Cui, Yumin,Ren, Yongxin,Fan, Shiming,Zhou, Jinghong,Qing, Weiguo,Gu, Yi,Wang, Jian,Sai, Yang,Su, Weiguo
-
supporting information
p. 7577 - 7589
(2014/12/11)
-
- A Novel 1,2,3,4-Tetrahydroquinoline Derivative Useful for the Treatment of Diabetes
-
The present invention provides a compound of the formula below or a pharmaceutical salt thereof, methods of treating diabetes using the compound and a process for preparing the compound.
- -
-
Page/Page column 8
(2013/03/26)
-
- CERTAIN TRIAZOLOPYRIDINES AND TRIAZOLOPYRAZINES, COMPOSITIONS THEREOF AND METHODS OF USE THEREFOR
-
Provided are certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor.
- -
-
Page/Page column 16
(2012/10/08)
-
- CERTAIN TRIAZOLOPYRIDINES AND TRIAZOLOPYRAZINES, COMPOSITIONS THEREOF AND METHODS OF USE THEREFOR
-
Provided are certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor.
- -
-
Page/Page column 29
(2011/07/30)
-
- AZOLE DERIVATIVES AS WTN PATHWAY INHIBITORS
-
The present invention relates to new compounds of formula I, to processes for their preparation, to pharmaceutical formulations containing such compounds and to their use in therapy. Such compounds find particular use in the treatment and/or prevention of conditions or diseases which are affected by over-activation of signaling in the Wnt pathway. For example, these may be used in preventing and/or retarding proliferation of tumor cells, for example carcinomas such as colon carcinomas.
- -
-
Page/Page column 129-130
(2010/12/29)
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- Synthesis of 2-thiophenecarboxylic and 2,5-thiophenedicarboxylic acid esters via the reaction of thiophenes with the CCl4-ROH reagent in the presence of vanadium, iron, and molybdenum catalysts
-
2-Thiophenecarboxylic and 2,5-thiohenedicarboxylic acid esters were synthesized via the reaction of thiophene with the CCl4-ROH-catalyst system, with a total yield of 44-85%. A possible reaction scheme includes the successive steps of alkylation of thiophene with carbon tetrachloride, leading to 2-trichloromethylthiophene, and alcoholysis of the product giving the corresponding 2-thiophenecarboxylate. The best catalysts for this reaction are VO(acac)2, Fe(acac)3, and Mo(CO)6.
- Khusnutdinov,Shchadneva,Baiguzina,Mukminov,Mayakova,Smirnov,Dzhemilev
-
experimental part
p. 471 - 478
(2010/03/31)
-
- Thienopyrrole compound and use thereof as HCV polymerase inhibitor
-
The present invention relates to a thienopyrrole compound represented by the following formula [I] wherein each symbol is as defined in the specification, or a pharmaceutically acceptable a salt thereof, and a hepatitis C virus (HCV) polymerase inhibitor and a therapeutic agent for hepatitis C containing this compound as an active ingredient. The compound of the present invention shows an anti-HCV activity based on the HCV polymerase inhibitory activity, and useful as an agent for the prophylaxis or treatment of hepatitis C.
- -
-
Page/Page column 154-155
(2008/06/13)
-
- 5-5-MEMBERED FUSED HETEROCYCLIC COMPOUND AND USE THEREOF AS HCV POLYMERASE INHIBITOR
-
The present invention relates to a fused ring compound represented by the following formula [I] wherein each symbol is as defined in the specification, or a pharmaceutically acceptable a salt thereof, and a hepatitis C virus (HCV) polymerase inhibitor and
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-
Page/Page column 131
(2008/06/13)
-
- PYRIDO PYRIMIDINONES, DIHYDRO PYRIMIDO PYRIMIDINONES AND PTERIDINONES USEFUL AS RAF KINASE INHIBITORS
-
The present invention provides compounds having the formula: (I) wherein A-B together represents one of the following structures; (II), (III), (IV) and n, R1, R2, R3, R4, L1, L2, Y and Z are as defined in classes and subclasses herein, and pharmaceutical compositions thereof, as described generally and in subclasses herein, which compounds are useful as inhibitors of protein kinase (e.g., RAF), and thus are useful, for example, for the treatment of RAF mediated diseases.
- -
-
Page/Page column 128
(2010/11/08)
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- Design, synthesis, and biological activity of novel, potent, and selective (benzoylaminomethyl)thiophene sulfonamide inhibitors of c-Jun-N-terminal kinase
-
Several lines of evidence support the hypothesis that c-Jun N-terminal kinases (JNKs) play a critical role in a wide range of disease states including cell death (apoptosis)-related and inflammatory disorders (epilepsy, brain, heart and renal ischemia, ne
- Rückle, Thomas,Biamonte, Marco,Grippi-Vallotton, Tania,Arkinstall, Steve,Cambet, Yves,Camps, Montserrat,Chabert, Christian,Church, Dennis J.,Halazy, Serge,Jiang, Xuliang,Martinou, Isabelle,Nichols, Anthony,Sauer, Wolfgang,Gotteland, Jean-Pierre
-
p. 6921 - 6934
(2007/10/03)
-
- Biaryloxymethylarenecarboxylic acids as glycogen synthase activator
-
The present invention relates to compounds of formula (I) wherein R1, R2, R3, R4, m, n, p and s are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases that are associated with the activation of the glycogen synthase enzyme, such as diabetes.
- -
-
Page/Page column 20; 21
(2010/02/10)
-
- Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design
-
The design, synthesis, and in vitro activities of a series of potent and selective small-molecule inhibitors of caspase-3 are described. From extended tethering, a salicylic acid fragment was identified as having binding affinity for the S4 pocket of caspase-3. X-ray crystallography and molecular modeling of the initial tethering hit resulted in the synthesis of 4, which reversibly inhibited caspase-3 with a Ki = 40 nM. Further optimization led to the identification of a series of potent and selective inhibitors with Ki values in the 20-50 nM range. One of the most potent compounds in this series, 66b, inhibited caspase-3 with a Ki = 20 nM and selectivity of 8-500-fold for caspase-3 vs a panel of seven caspases (1, 2, and 4-8). A high-resolution X-ray cocrystal structure of 4 and 66b supports the predicted binding modes of our compounds with caspase-3.
- Choong, Ingrid C.,Lew, Willard,Lee, Dennis,Pham, Phuongly,Burdett, Matthew T.,Lam, Joni W.,Wiesmann, Christian,Luong, Tinh N.,Fahr, Bruce,DeLano, Warren L.,McDowell, Robert S.,Allen, Darin A.,Erlanson, Daniel A.,Gordon, Eric M.,O'Brien, Tom
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p. 5005 - 5022
(2007/10/03)
-
- Antiviral thiazoles
-
Compounds of formula (I) are active antiviral compounds useful in the treatment of viral infections in mammals. The compounds of the invention are readily prepared by reaction of a suitable 2-thiothiazole derivative with an appropriate Het-(CH2)n -halide.
- -
-
-
- A New Indirect Application of Aggregative Activation: Synthesis of Esters by Cobalt-Catalyzed Carbonylation of Aryl, Heterocyclic, and Vinyl Halides under Atmospheric Pressure
-
Sun lamp illuminated alkoxycarbonylation of aryl, heteroaryl, and vinyl halides was performed under atmospheric pressure of CO in the presence of a cobalt catalyst in situ generated from Co(OAc)2.Illunination through a Pyrex flask was sufficient to catalyze the reaction.This process avoids the use of Co2(CO)8 and excess CH3I, which were required in the earlier procedure.A SRN1 mechanism is proposed.
- Marchal, Joel,Bodiguel, Jacques,Fort, Yves,Caubere, Paul
-
p. 8336 - 8340
(2007/10/02)
-
- SIMPLE PREPARATION OF METHYL 4-CHLOROMETHYL- AND METHYL 5-CHLOROMETHYL-2-THIOPHENECARBOXYLATE
-
Selective reduction of a mixture of methyl 4-chloromethyl-2-thiophenecarboxylate (I) and the 5-chloromethyl isomer II, prepared by chloromethylation of methyl 2-thiophenecarboxylate (III), gave pure 4-chloromethyl derivative I and 5-methyl-2-thiophenecarboxylate (V) which on treatment with sulfuryl chloride was converted into the 5-chloromethyl isomer II.
- Kozmik, Vaclav,Palecek, Jaroslav
-
p. 1483 - 1486
(2007/10/02)
-