- Steric effect of NHC ligands in Pd(II)–NHC-catalyzed non-directed C–H acetoxylation of simple arenes
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Although there has been a lot of progress in oxidative arene C–H functionalization reactions catalyzed by Pd(II/IV) system, the non-directed, site-selective functionalization of arene molecules is still challenging. It has been established that ligands play a pivotal role in controlling rate- as well as selectivity-determining step in a catalytic cycle involving well-defined metal-ligand bonding. N-heterocyclic carbene (NHC) ligands have had a tremendous contribution in the recent extraordinary success of achieving high reactivity and excellent selectivity in many catalytic processes including cross-coupling and olefin-metathesis reactions. However, the immense potential of these NHC ligands in improving site-selectivity of non-directed catalytic C–H functionalization reactions of simple arenes is yet to be realized, where overriding the electronic bias on deciding selectivity is a burdensome task. The presented work demonstrated an initiative step in this regard. Herein, a series of well-defined discrete [Pd(NHCR′R)(py)I2] complexes with systematically varied degree of spatial congestion at the Pd centre, exerted through the R and R’ substituents on the NHC ligand, were explored in controlling the activity as well as the site-selectivity of non-directed acetoxylation of representative monosubstituted and disubstituted simple arenes (such as toluene, iodobenzene and bromobenzene, naphthalene and 1,2-dichlorobenzene). The resulting best yields were found to be 75% for toluene and 65% for bromobenzene with [Pd(NHCMePh)(py)I2], 75% for iodobenzene and 79% for naphthalene with [Pd(NHCMeMe)(py)I2], and 41% for 1,2-dichlorobenzene with [Pd(NHCCyCy)(py)I2]. Most importantly, with increasing the bulkiness of the NHC ligand in the complexes, the selectivity of the distal C-acetoxylated products in comparison to the proximal ones, was enhanced to a great extent in all cases. Considering the vast library of NHC ligands, this study underscores the future opportunity to develop more strategies to improve the activity and the crucial site-selectivity of C–H functionalization reactions in simple as well as complex organic molecules.
- Mandal, Tanmoy,Yadav, Sudha,Choudhury, Joyanta
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- Enantioselective Intermolecular C-H Amination Directed by a Chiral Cation
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The enantioselective amination of C(sp3)-H bonds is a powerful synthetic transformation yet highly challenging to achieve in an intermolecular sense. We have developed a family of anionic variants of the best-in-class catalyst for Rh-catalyzed C-H amination, Rh2(esp)2, with which we have associated chiral cations derived from quaternized cinchona alkaloids. These ion-paired catalysts enable high levels of enantioselectivity to be achieved in the benzylic C-H amination of substrates bearing pendant hydroxyl groups. Additionally, the quinoline of the chiral cation appears to engage in axial ligation to the rhodium complex, providing improved yields of product versus Rh2(esp)2 and highlighting the dual role that the cation is playing. These results underline the potential of using chiral cations to control enantioselectivity in challenging transition-metal-catalyzed transformations.
- Fanourakis, Alexander,Paterson, Kieran J.,Phipps, Robert J.,Williams, Benjamin D.
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supporting information
p. 10070 - 10076
(2021/07/21)
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- Dibenzofuran derivatives inspired from cercosporamide as dual inhibitors of pim and CLK1 kinases
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Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b, d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure-activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.
- Bach, Stéphane,Baratte, Blandine,Bazin, Marc-Antoine,Brachet-Botineau, Marie,Dao, Viet Hung,Denevault-Sabourin, Caroline,Gouilleux, Fabrice,Logé, Cédric,Marchand, Pascal,McCarthy, Florence O.,Ourliac-Garnier, Isabelle,Robert, Thomas,Thiéfaine, Jér?me,da Silva, Teresinha Gon?alves
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- Extended Naphthalene Diimides with Donor/Acceptor Hydrogen-Bonding Properties Targeting G-Quadruplex Nucleic Acids
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Naphthalene diimides with one or two centrosymmetric arylethynyl moieties capable of synergic donor and acceptor hydrogen bonding exhibit promising binding properties and selectivity towards parallel G-quadruplex (G4) nucleic acids (c-myc, bcl-2 and parallel hTel22). The hydrogen-bonding network involving the phosphate backbone and outside rim of the G-quartet represents an opportunity to exploit G4 selectivity for extended aromatics.
- Doria, Filippo,Nadai, Matteo,Costa, Giosuè,Sattin, Giovanna,Gallati, Caroline,Bergamaschi, Greta,Moraca, Federica,Alcaro, Stefano,Freccero, Mauro,Richter, Sara N.
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p. 4824 - 4833
(2016/10/13)
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- Aryl ethynyl anthraquinones: A useful platform for targeting telomeric G-quadruplex structures
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Aryl ethynyl anthraquinones have been synthesized by Sonogashira cross-coupling and evaluated as telomeric G-quadruplex ligands, by the FRET melting assay, circular dichroism, the DNA synthesis arrest assay and molecular docking. Both the binding properti
- Percivalle, Claudia,Sissi, Claudia,Greco, Maria Laura,Musetti, Caterina,Mariani, Angelica,Artese, Anna,Costa, Giosuè,Perrore, Maria Lucia,Alcaro, Stefano,Freccero, Mauro
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supporting information
p. 3744 - 3754
(2014/06/09)
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- TRICYCLIC COMPOUNDS AS mPGES-1 INHIBITORS
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The present invention relates to tricyclic compounds of formula (I) or pharmaceutically acceptable salt thereof as mPGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthama, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases. (I)
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Page/Page column 34; 78
(2012/09/10)
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- COMPOUND
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The present invention provides compounds of the formula Formula I or a salt thereof: and the uses of such compounds for the treatment of a disease or disorder involving oxidative damage, for preventing UV damage to the skin of a mammal and for preventing or reversing the effects of ageing, or for treating or preventing dry skin.
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Page/Page column 43
(2012/05/04)
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- Silver triflate catalyzed acetylation of alcohols, thiols, phenols, and amines
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A variety of alcohols, thiols, phenols, and amines were subjected to acetylation reaction using acetic anhydride in the presence of catalytic quantity of silver triflate. The method described has a wide range of applications, proceeds under mild conditions, does not involve cumbersome workup, and the resulting products are obtained in high yields within a reasonable time. Georg Thieme Verlag Stuttgart · New York.
- Das, Rima,Chakraborty, Debashis
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experimental part
p. 1621 - 1625
(2011/06/25)
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- Design, synthesis, and biological evaluation of novel potent and selective αvβ3/αvβ5 integrin dual inhibitors with improved bioavailability. Selection of the molecular core
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A novel series of potent and selective αvβ 3/αvβ5 dual inhibitors was designed, synthesized, and evaluated against several integrins. These compounds were synthesized through a Mitsunobu reaction between the gua
- Marugán, Juan José,Manthey, Carl,Anaclerio, Beth,Lafrance, Lou,Lu, Tianbao,Markotan, Tom,Leonard, Kristi A.,Crysler, Carl,Eisennagel, Stephen,Dasgupta, Malini,Tomczuk, Bruce
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p. 926 - 934
(2007/10/03)
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- Diflunisal Analogues Stabilize the Native State of Transthyretin. Potent Inhibition of Amyloidogenesis
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Analogues of diflunisal, an FDA-approved nonsteroidal antiinflammatory drug (NSAID), were synthesized and evaluated as inhibitors of transthyretin (TTR) aggregation, including amyloid fibril formation. High inhibitory activity was observed for 26 of the compounds. Of those, eight exhibited excellent binding selectivity for TTR in human plasma (binding stoichiometry > 0.50, with a theoretical maximum of 2.0 inhibitors bound per TTR tetramer). Biophysical studies reveal that these eight inhibitors dramatically slow tetramer dissociation (the rate-determining step of amyloidogenesis) over a duration of 168 h. This appears to be achieved through ground-state stabilization, which raises the kinetic barrier for tetramer dissociation. Kinetic stabilization of WT TTR by these eight inhibitors is further substantiated by the decreasing rate of amyloid fibril formation as a function of increasing inhibitor concentration (pH 4.4). X-ray cocrystal structures of the TTR·182 and TTR·202 complexes reveal that 18 and 20 bind in opposite orientations in the TTR binding site. Moving the fluorines from the meta positions in 18 to the ortho positions in 20 reverses the binding orientation, allowing the hydrophilic aromatic ring of 20 to orient in the outer binding pocket where the carboxylate engages in favorable electrostatic interactions with the ε-ammonium groups of Lys 15 and 15′. The hydrophilic aryl ring of 18 occupies the inner binding pocket, with the carboxylate positioned to hydrogen bond to the serine 117 and 117′ residues. Diflunisal itself appears to occupy both orientations based on the electron density in the TTR·12 structure. Structure-activity relationships reveal that para-carboxylate substitution on the hydrophilic ring and dihalogen substitution on the hydrophobic ring afford the most active TTR amyloid inhibitors.
- Adamski-Werner, Sara L.,Palaninathan, Satheesh K.,Sacchettini, James C.,Kelly, Jeffery W.
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p. 355 - 374
(2007/10/03)
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- Potential therapeutic antioxidants that combine the radical scavenging ability of myricetin and the lipophilic chain of vitamin E to effectively inhibit microsomal lipid peroxidation
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The flavonol myricetin, reacts with oxygen-centred galvinoxyl radicals 28 times faster than d-α-tocopherol (vitamin E), the main lipid-soluble antioxidant in biological membranes. Moreover, each myricetin molecule reduces twice as many such radicals as vitamin E. However, myricetin fails to protect vitamin E-deficient microsomes from lipid peroxidation as assessed by the formation of thiobarbituric acid reactive substances (TBARS). Novel and potentially therapeutic antioxidants have been prepared that combine the radical-scavenging ability of a myricetin-like head group with a lipophilic chain similar to that of vitamin E. C6-C12 alkyl chains are attached to the A-ring of either a 3,3′,4 ′,5′-tetrahydroxyflavone or a 3,2 ′,4′,5′-tetrahydroxyflavone head group to give lipophilic flavonoids (ClogP=4 to 10) that markedly inhibit iron-ADP catalysed oxidation of microsomal preparations. Orientation of the head group as well as total lipophilicity are important determinants of antioxidant efficacy. MM2 models indicate that our best straight chain 7-alkylflavonoids embed to the same depth in the membrane as vitamin E. The flavonoid head groups are prepared by aldol condensation followed by Algar-Flynn-Oyamada (AFO) oxidation or by Baker-Venkataraman rearrangement. The alkyl tails are introduced by Suzuki or Negishi palladium-catalysed cross-coupling or by cross-metathesis catalysed by first generation Grubbs catalyst, which tolerate phenolic hydroxyl and ketone groups.
- Bennett, Christopher J.,Caldwell, Stuart T.,McPhail, Donald B.,Morrice, Philip C.,Duthie, Garry G.,Hartley, Richard C.
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p. 2079 - 2098
(2007/10/03)
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- Substituted benzofurans and benzothiophenes, methods of making and methods of use as integrin antagonists
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The present invention relates to novel substituted benzofurans and benzothiophenes compounds that are antagonists of alpha V (αv) integrins, for example αvβ3 and αvβ5 integrins, their pharmaceutically acceptable
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- Antimuscarinic 3-(2-Furanyl)quinuclidin-2-ene derivatives: Synthesis and structure-activity relationships
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A series of 25 derivatives of the muscarinic antagonist 3-(2- furanyl)quinuclidin-2-ene (4) was synthesized and evaluated for muscarinic and antimuscarinic properties. Substitution at all three positions of the furan ring has been investigated. The affini
- Johansson, Gary
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p. 3804 - 3819
(2007/10/03)
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