- Harnessing affinity-based protein profiling to reveal a novel target of nintedanib
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Nintedanib (BIBF1120), a triple angiokinase inhibitor, was first approved for idiopathic pulmonary fibrosis (IPF) therapy and is also efficacious for lung carcinoma, and interstitial lung diseases, far beyond its inhibition of VEGFR/PDGFR/FGFR. We identified tripeptidyl-peptidase 1 (TPP1) as one of the direct targets of nintedanib employing the affinity-based protein profiling (AfBPP) technique. This may be a new mechanism for nintedanib's role different from tyrosine kinase inhibition.
- Chen, Xiong,Li, Manru,Li, Menglin,Wang, Dongmei,Zhang, Jinlan
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p. 3139 - 3142
(2021/04/02)
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- Regioselective Radical Arene Amination for the Concise Synthesis ofortho-Phenylenediamines
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The formation of arene C-N bonds directly from C-H bonds is of great importance and there has been rapid recent development of methods for achieving this through radical mechanisms, often involving reactiveN-centered radicals. A major challenge associated with these advances is that of regiocontrol, with mixtures of regioisomeric products obtained in most protocols, limiting broader utility. We have designed a system that utilizes attractive noncovalent interactions between an anionic substrate and an incoming radical cation in order to guide the latter to the areneorthoposition. The anionic substrate takes the form of a sulfamate-protected aniline and telescoped cleavage of the sulfamate group after amination leads directly toortho-phenylenediamines, key building blocks for a range of medicinally relevant diazoles. Our method can deliver both free amines and monoalkyl amines allowing access to unsymmetrical, selectively monoalkylated benzimidazoles and benzotriazoles. As well as providing concise access to valuableortho-phenylenediamines, this work demonstrates the potential for utilizing noncovalent interactions to control positional selectivity in radical reactions.
- Gillespie, James E.,Morrill, Charlotte,Phipps, Robert J.
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supporting information
p. 9355 - 9360
(2021/07/19)
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- Virtual screening guided design, synthesis and bioactivity study of benzisoselenazolones (BISAs) on inhibition of c-met and its downstream signalling pathways
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c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In this study, we designed a small library containing 300 BISAs molecules that consisted of carbohydrates, amino acids, isothiourea, tetramethylthiourea, guanidine and heterocyclic groups and screened c-Met targeting compounds using docking and MM/GBSA. Guided by virtual screening, we synthesised a series of novel compounds and their activity on inhibition of the autophosphorylation of c-Met and its downstream signalling pathway proteins were evaluated. We found a panel of benzisoselenazolones (BISAs) obtained by introducing isothiourea, tetramethylthiourea and heterocyclic groups into the C-ring of Ebselen, including 7a, 7b, 8a, 8b and 12c (with IC50 values of less than 20 μMin MET gene amplified lung cancer cell line EBC-1), exhibited more potent antitumour activity than Ebselen by cell growth assay combined with in vitro biochemical assays. In addition, we also tested the antitumour activity of three cancer cell lines without MET gene amplification/activation, including DLD1, MDA-MB-231 and A549. The neuroblastoma SK-N-SH cells with HGF overexpression which activates MET signalling are sensitive to MET inhibitors. The results reveal that our compounds may be nonspecific multitarget kinase inhibitors, just like type-II small molecule inhibitors. Western blot analysis showed that these inhibitors inhibited autophosphorylation of c-MET, and its downstream signalling pathways, such as PI3K/AKT and MARK/ERK. Results suggest that bensoisoselenones can be used as a scaffold for the design of c-Met inhibiting drug leads, and this study opens up new possibilities for future antitumour drug design.
- Zhang, Siqi,Song, Qiaoling,Wang, Xueting,Wei, Zhiqiang,Yu, Rilei,Wang, Xin,Jiang, Tao
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- STABILIZATION OF ACTIVE METAL CATALYSTS AT METAL-ORGANIC FRAMEWORK NODES FOR HIGHLY EFFICIENT ORGANIC TRANSFORMATIONS
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Metal-organic framework (MOFs) compositions based on post?synthetic metalation of secondary building unit (SBU) terminal or bridging OH or OH2 groups with metal precursors or other post-synthetic manipulations are described. The MOFs provide a versatile family of recyclable and reusable single-site solid catalysts for catalyzing a variety of asymmetric organic transformations, including the regioselective boryiation and siiylation of benzyiic C—H bonds, the hydrogenation of aikenes, imines, carbonyls, nitroarenes, and heterocycles, hydroboration, hydrophosphination, and cyclization reactions. The solid catalysts can also be integrated into a flow reactor or a supercritical fluid reactor.
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Paragraph 0354-0356; 0359
(2019/01/07)
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- Single-Site Cobalt Catalysts at New Zr12(μ3-O)8(μ3-OH)8(μ2-OH)6 Metal-Organic Framework Nodes for Highly Active Hydrogenation of Nitroarenes, Nitriles, and Isocyanides
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We report here the synthesis of a robust and porous metal-organic framework (MOF), Zr12-TPDC, constructed from triphenyldicarboxylic acid (H2TPDC) and an unprecedented Zr12 secondary building unit (SBU): Zr12(μ3-O)8(μ3-OH)8(μ2-OH)6. The Zr12-SBU can be viewed as an inorganic node dimerized from two commonly observed Zr6 clusters via six μ2-OH groups. The metalation of Zr12-TPDC SBUs with CoCl2 followed by treatment with NaBEt3H afforded a highly active and reusable solid Zr12-TPDC-Co catalyst for the hydrogenation of nitroarenes, nitriles, and isocyanides to corresponding amines with excellent activity and selectivity. This work highlights the opportunity in designing novel MOF-supported single-site solid catalysts by tuning the electronic and steric properties of the SBUs.
- Ji, Pengfei,Manna, Kuntal,Lin, Zekai,Feng, Xuanyu,Urban, Ania,Song, Yang,Lin, Wenbin
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p. 7004 - 7011
(2017/05/31)
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- Methanol dehydrogenation by iridium N-heterocyclic carbene complexes
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A series of homogeneous iridium bis(N-heterocyclic carbene) catalysts are active for three transformations involving dehydrogenative methanol activation: acceptorless dehydrogenation, transfer hydrogenation, and amine monoalkylation. The acceptorless dehydrogenation reaction requires base, yielding formate and carbonate, as well as 2-3 equivalents of H2. Of the few homogeneous systems known for this reaction, our catalysts tolerate air and employ simple ligands. Transfer hydrogenation of ketones and imines from methanol is also possible. Finally, N-monomethylation of anilines occurs through a borrowing hydrogen reaction. Notably, this reaction is highly selective for the monomethylated product.
- Campos, Jesús,Sharninghausen, Liam S.,Manas, Michael G.,Crabtree, Robert H.
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p. 5079 - 5084
(2015/06/16)
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- Room-temperature copper-catalyzed arylation of dimethylamine and methylamine in neat water
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The first room-temperature copper-catalyzed arylations of dimethylamine and methylamine in neat water have been developed. Using a combination of CuI and 6,7-dihydroquinolin-8(5 H)-one oxime as catalyst, dimethylamine is arylated with various aryl halides to give the corresponding products in good to excellent yields. Further, this catalysis enables the selective arylation of methylamine to afford the high yields of monoarylated methylamines as the sole products.
- Wang, Deping,Kuang, Daizhi,Zhang, Fuxing,Yang, Chunlin,Zhu, Xiaoming
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supporting information
p. 714 - 718
(2015/03/18)
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- Catalytic methylation of aromatic amines with formic acid as the unique carbon and hydrogen source
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A novel methodology is presented for the direct methylation of amines, using formic acid as a unique source of carbon and hydrogen. Based on ruthenium(II) catalysts, the formation of the N - CH3group proceeds via an efficient formylation/transfer hydrogenation pathway.
- Savourey, Solne,Lefvre, Guillaume,Berthet, Jean-Claude,Cantat, Thibault
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supporting information
p. 14033 - 14036
(2015/02/19)
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- Mild and highly selective palladium-catalyzed monoarylation of ammonia enabled by the use of bulky biarylphosphine ligands and palladacycle precatalysts
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A method for the Pd-catalyzed arylation of ammonia with a wide range of aryl and heteroaryl halides, including challenging five-membered heterocyclic substrates, is described. Excellent selectivity for monoarylation of ammonia to primary arylamines was achieved under mild conditions or at rt by the use of bulky biarylphosphine ligands (L6, L7, and L4) as well as their corresponding aminobiphenyl palladacycle precatalysts (3a, 3b, and 3c). As this process requires neither the use of a glovebox nor high pressures of ammonia, it should be widely applicable.
- Cheung, Chi Wai,Surry, David S.,Buchwald, Stephen L.
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supporting information
p. 3734 - 3737
(2013/08/23)
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- a2-Adrenoceptor Ligands
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The adrenergic receptors or adrenoceptors are a family of G-protein coupled receptors split into α and β subclasses. The adrenoceptors have important roles in regulating a myriad of physiological conditions and their malfunction has been implicated in the pathophysiology of a number of diseases. Disclosed herein are a series of novel compounds which are ligands of the alpha2-adrenoceptor (α2-ARs) subclass of adrenergic receptors. The invention also provides for pharmaceutical compositions comprising the novel compounds. The compounds are suitable for use in the manufacture of medicaments for the treatment of α2-ARs associated disorders, such as depression and schizophrenia.
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Page/Page column 7
(2010/07/04)
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- Guanidine and 2-aminoimidazoline aromatic derivatives as α2-adrenoceptor ligands: Searching for structure-activity relationships
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In this paper, we report the synthesis of three new 2-aminoimidazoline (compounds 4b, 5b, and 6b) and three new guanidine derivatives (compounds 7b, 8b, and 9b) as potential α2-adrenoceptor antagonists for the treatment of depression. Their pha
- Rodriguez, Fernando,Rozas, Isabel,Ortega, Jorge E.,Erdozain, Amaia M.,Meana, J. Javier,Callado, Luis F.
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experimental part
p. 601 - 609
(2009/11/30)
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- Arylisothiocyanato selective androgen receptor modulators (SARMs) for prostate cancer
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A new series of androgen receptor targeted agents (ARTA) was prepared and tested in androgen-dependent and -independent prostate cancer cell lines. These agents were bicalutamide analogs with isothiocyanato substituted B-rings. Also, the linker sulfone of R-bicalutamide was maintained or replaced with several alternative linkages including ether, amine, N-methylamine, thioether, and methylene (in this case the product was a racemic mixture) functional groups at the X-position. To expand the structure-activity relationship (SAR) of these arylisothiocyanato AR ligands, B-ring halogenated arylisothiocyanato ligands were also prepared and tested. The arylisothiocyanato AR ligands showed strong binding affinities to AR ranging from 0.6 to 54 nM. Among them, thioether and ether linkages demonstrated high binding affinities (0.6 and 4.6 nM, respectively) and selective cell growth inhibition (approximately 3- to 6-fold) for LNCaP, an androgen-dependent prostate cancer cell line, when compared to the androgen independent prostate cell lines (DU145, PC-3, and PPC-1) and a bladder cell line (TSU-Pr1). However, the ligands were inactive (IC50>100 mM) in a normal monkey kidney cell line (CV-1) that was used as the control for non-specific toxicity.
- Hwang, Dong Jin,Yang, Jun,Xu, Huiping,Rakov, Igor M.,Mohler, Michael L.,Dalton, James T.,Miller, Duane D.
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p. 6525 - 6538
(2007/10/03)
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- Azo-functionalized dendrimers
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We report the synthesis of azo-functionalized Starburst polyamidoamine (PAMAM) dendrimers. The following three systems of azo-functionalized PAMAM dendrimers were prepared by different synthetic routes: (i) phenylazo derivatives; (ii) naphthalimide azo derivatives; and (iii) phthalimide azo derivatives. Model compounds in each system were synthesized for spectroscopic comparison. Confirmation of structure was achieved using a combination of NMR and IR spectroscopy to ascertain the functional sites (i.e., the azo and the cyclic imides), while mass spectrometry and UV-vis spectrophotometry were employed to ascertain the extent of functionalization. Substitution by the azo pendent groups increased the thermal stability of PAMAM dendrimers (TGA weight loss of the naphthalimide azo-functionalized PAMAM dendrimers up to 300°C, ca. 5%).
- Cheon, Kap-Soo,Kazmaier, Peter M.,Keum, Sam-Rok,Park, Kuk-Tae,Buncel, Erwin
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p. 551 - 566
(2007/10/03)
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- Reduction of nitrosoarenes into anilines by Al/NH4Cl in refluxing methanol
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A simple, cost-effective method for the reduction of nitrosoarenes by aluminium in the presence of ammonium chloride in refluxing methanol to give anilines is reported.
- Nagaraja,Pasha
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p. 593 - 594
(2007/10/03)
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- Method for preparing aromatic secondary amino compound
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Disclosed are (1) a method for preparing an aromatic secondary amino compound which comprises reacting an N-cyclohexylideneamino compound in the presence of a hydrogen moving catalyst and a hydrogen acceptor by the use of a sulfur-free polar solvent and/or a cocatalyst, and (2) a method for preparing an aromatic secondary amino compound which comprises reacting cyclohexanone or a nucleus-substituted cyclohexanone, an amine and a nitro compound corresponding to the amine in a sulfur-free polar solvent in the presence of a hydrogen moving catalyst, a cocatalyst being added or not added. In a further aspect, a method is provided for the preparation of aminodiphenylamine by reacting phenylenediamine and cyclohexanone in the presence of a hydrogen transfer catalyst in a sulfur-free polar solvent while using nitroaniline as a hydrogen acceptor.
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- Method for preparing aromatic secondary amino compound
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Disclosed are (1) a method for preparing an aromatic secondary amino compound which comprises reacting an N-cyclohexylideneamino compound in the presence of a hydrogen moving catalyst and a hydrogen acceptor by the use of a sulfur-free polar solvent and/or a cocatalyst, and (2) a method for preparing an aromatic secondary amino compound which comprises reacting cyclohexanone or a nucleus-substituted cyclohexanone, an amine and a nitro compound corresponding to the amine in a sulfur-free polar solvent in the presence of a hydrogen moving catalyst, a cocatalyst being added or not added.
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- Process for dyeing keratinous fibres with oxidation bases combined with an iodide and dyeing composition employed
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A process for dyeing keratinous fibers employs a dye composition containing an oxidation base selected from a paraphenylenediamine, an N,N'-diphenylalkylene diamine, a para-aminophenol, an ortho-aminophenol, an ortho-phenylenediamine or a heterocyclic oxidation base, in combination with iodide ions. The application of this dyeing composition to the keratinous fibers is preceded or followed by the application to the fibers of a composition containing hydrogen peroxide.
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