- Photochemical and Thermal Hydrations of Aromatic Allenes. Evidence for Allyl and Vinyl Cation Intermediates
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The photohydration of aromatic allenes has been studied in water and in dilute aqueous sulfuric acid (0-25percent H2SO4).It was found that phenylallene (2a) and α-methylphenylallene (2b) undergo photohydration to give the corresponding cinnamyl alcohol derivatives.The proposed mechanism involves protonation of the central carbon of phenylallenes in their singlet excited state (S1).In contrast, (p-nitrophenyl)allene (2g) and (m-nitrophenyl)allene (2h) gave the corresponding (nitrophenyl)acetones.The mechanism for the formation of these ketones is believed to be due to initial protonation of the α- or γ-carbon atom of the (nitrophenyl)allene in the triplet excited state (T1).Phenylallenes with CN, CF3, and F substituents failed to photohydrate.The results of these photohydrations were compared with those of the much slower thermal hydrations in 70-83percent H2SO4.Phenylallenes 2a and 2b cyclized to the corresponding indene derivatives in 70percent H2SO4.Phenylallenes with NO2-substituents (2g-2h) underwent hydration to give the corresponding (nitrophenyl)acetones (expected products) and (nitrophenyl)-1-propanones (unexpected products) in 83percent H2SO4.Similar results were obtained with (m-cyanophenyl)allene.The formation of both types of ketone is discussed in terms of the intermediacy of a common vinyl cation intermediate.
- Rafizadeh, Karim,Yates, Keith
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- Substituted dienes prepared from betulinic acid – Synthesis, cytotoxicity, mechanism of action, and pharmacological parameters
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A set of new substituted dienes were synthesized from betulinic acid by its oxidation to 30-oxobetulinic acid followed by the Wittig reaction. Cytotoxicity of all compounds was tested in vitro in eight cancer cell lines and two noncancer fibroblasts. Almost all dienes were more cytotoxic than betulinic acid. Compounds 4.22, 4.30, 4.33, 4.39 had IC50 below 5 μmol/L; 4.22 and 4.39 were selected for studies of the mechanism of action. Cell cycle analysis revealed an increase in the number of apoptotic cells at 5 × IC50 concentration, where activation of irreversible changes leading to cell death can be expected. Both 4.22 and 4.39 led to the accumulation of cells in the G0/G1 phase with partial inhibition of DNA/RNA synthesis at 1 × IC50 and almost complete inhibition at 5 × IC50. Interestingly, compound 4.39 at 5 × IC50 caused the accumulation of cells in the S phase. Higher concentrations of tested drugs probably inhibit more off-targets than lower concentrations. Mechanisms disrupting cellular metabolism can induce the accumulation of cells in the S phase. Both compounds 4.22 and 4.39 trigger selective apoptosis in cancer cells via intrinsic pathway, which we have demonstrated by changes in the expression of the crucial apoptosis-related protein. Pharmacological parameters of derivative 4.22 were superior to 4.39, therefore 4.22 was the finally selected candidate for the development of anticancer drug.
- Frydrych, Ivo,Urban, Milan,?arek, Jan,Benická, Sandra,D?ubák, Petr,Gurská, Soňa,Hajdúch, Marián,Kotulová, Jana,Li?ková, Barbora,Olejníková, Denisa,Pokorny, Jan
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- Site-Selective Nitrene Transfer to Conjugated Olefins Directed by Oxazoline Peptide Ligands
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Site-selective nitrene transfer to di- and polyene substrates has been achieved using designed peptide-embedded bioxazoline ligands capable of binding copper. In model 1,3-diene substrates, the olefinic position proximal to a directing group was selectively functionalized. Additional studies indicate that this selectivity stems from non-covalent substrate-catalyst interactions. The peptide-mediated nitrene transfer was also applied to polyene natural product retinol and selective proximal functionalization allowed access to a cis-pyrroline modified retinoid. (Figure presented.).
- Storch, Golo,van den Heuvel, Naudin,Miller, Scott J.
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supporting information
p. 289 - 294
(2019/08/30)
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- NOVEL CYCLOSPORIN DERIVATIVES AND USES THEREOF
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A compound of the Formula (I) is disclosed: (I) or pharmaceutically acceptable salt thereof, wherein the symbols are as defined in the specification. Also described are a pharmaceutical composition comprising the same and a method for treating or preventing viral infections, inflammation, dry eye, central nervous disorders, cardiovascular diseases, cancer, obesity, diabetes, muscular dystrophy, lung, and liver, and kindey diseases, and hair loss using the same.
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Paragraph 0179
(2017/12/18)
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- Potent and selective double-headed thiophene-2-carboximidamide inhibitors of neuronal nitric oxide synthase for the treatment of melanoma
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Selective inhibitors of neuronal nitric oxide synthase (nNOS) are regarded as valuable and powerful agents with therapeutic potential for the treatment of chronic neurodegenerative pathologies and human melanoma. Here, we describe a novel hybrid strategy
- Huang, He,Li, Huiying,Yang, Sun,Chreifi, Georges,Martásek, Pavel,Roman, Linda J.,Meyskens, Frank L.,Poulos, Thomas L.,Silverman, Richard B.
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p. 686 - 700
(2014/03/21)
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- Thiophene-2-carboximidamide Based Selective Neuronal Nitric Oxide Inhibitors
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Selective neuronal nitric oxide synthase (nNOS) inhibitor compounds designed with one or more thiophene-2-carboximidamide substituents for improved bioavailability.
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Paragraph 0028
(2014/03/25)
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- Synthesis of fluorinated analogues of sphingosine-1-phosphate antagonists as potential radiotracers for molecular imaging using positron emission tomography
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Sphingosine-1-phosphate (S1P) receptors play major roles in cardiovascular, immunological and neurological diseases. The recent approval of the sphingolipid drug Fingolimod (Gilenya), a sphingosine-1-phosphate agonist for relapsing multiple sclerosis, in 2010 exemplifies the potential for targeting sphingolipids for the treatment of human disorders. Moreover, non-invasive in vivo imaging of S1P receptors that are not available till now would contribute to the understanding of their role in specific pathologies and is therefore of preclinical interest. Based on fluorinated analogues of the S1P1receptor antagonist W146 showing practically equal in vitro potency as the lead structure, the first S1P receptor antagonist [18F]-radiotracer has been synthesized and tested for in vivo imaging of the S1P1receptor using positron emission tomography (PET). Though the tracer is serum stable, initial in vivo images show fast metabolism and subsequent accumulation of free [18F]fluoride in the bones.
- Prasad, Vysakh Pushpa,Wagner, Stefan,Keul, Petra,Hermann, Sven,Levkau, Bodo,Sch?fers, Michael,Haufe, Günter
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p. 5168 - 5181
(2015/02/19)
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- Importance of direct metal-π coupling in electronic transport through conjugated single-molecule junctions
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We study the effects of molecular structure on the electronic transport and mechanical stability of single-molecule junctions formed with Au point contacts. Two types of linear conjugated molecular wires are compared: those functionalized with methylsulfi
- Meisner, Jeffrey S.,Ahn, Seokhoon,Aradhya, Sriharsha V.,Krikorian, Markrete,Parameswaran, Radha,Steigerwald, Michael,Venkataraman, Latha,Nuckolls, Colin
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supporting information
p. 20440 - 20445
(2013/02/25)
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- Bidirectional photocontrol of peptide conformation with a bridged azobenzene derivative
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It goes both ways: A thiol-reactive cross-linker based on a bridged azobenzene derivative permits photoreversible control of peptide conformation on irradiation with violet (407a nm) and green (500-550a nm) light (see picture) through isomerization of the
- Samanta, Subhas,Qin, Chuanguang,Lough, Alan J.,Woolley, G. Andrew
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supporting information; experimental part
p. 6452 - 6455
(2012/07/27)
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- PYRIDONE COMPOUND
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The present inventors have conducted extensive studies on an EP4 receptor agonist, and as a result, found that a novel pyridone compound characterized in that the 1-position in the pyridone ring is substituted with a group having an acidic group such as a
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Page/Page column 38; 61
(2010/03/04)
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- N-Phenyl-N′-(2-chloroethyl)urea analogues of combretastatin A-4: Is the N-phenyl-N′-(2-chloroethyl)urea pharmacophore mimicking the trimethoxy phenyl moiety?
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A series of novel N-phenyl-N′-(2-chloroethyl)urea derivatives potentially mimicking the structure of combretastatin A-4 were synthesized and tested for their cell growth inhibition and their binding to the colchicine-binding site of β-tubulin. Compounds 2a, 3a, and 3b were found to inhibit cell growth at the micromolar level on four human tumor cell lines. Flow cytometric analysis indicates that the new compounds act as antimitotics and arrest the cell cycle in G2/M phase. Covalent binding of 2a, 3a, and 3b to the colchicine-binding site of β-tubulin was confirmed also using SDS-PAGE and competition assays.
- Fortin, Sebastien,Moreau, Emmanuel,Lacroix, Jacques,Teulade, Jean-Claude,Patenaude, Alexandre,C-Gaudreault, Rene
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p. 2000 - 2004
(2008/02/04)
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- The reaction of peroxynitrite with organic molecules bearing a biologically important functionality. The multiplicity of reaction modes as exemplified by hydroxylation, nitration, nitrosation, dealkylation, oxygenation, and oxidative dimerization and cleavage
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The reactions of peroxynitrite with a variety of organic molecules which include a biologically important functionality have been examined to construct a simple model for the peroxynitrite-induced in vivo transformations as well as a chemical probe for the active species involved therein. Phenols were found to undergo hydroxylation, nitration, oxidative dimerization, and oxidation to cyclohexadienones and quinones. The ring nitration of catechol was confirmed for the first time in the in vitro reaction of peroxynitrite. Dealkylation and N-oxide formation were the major reaction modes observed for N,N-dimethyl-p-toluidine. 1,2-Phenylenediamine gave benzotriazole in high yield. The electron-deficient C-C double bond in 1,4-naphthoquinone underwent epoxidation, while the electron-rich C-C double bond in α-methylstyrene suffered oxidative cleavage to acetophenone. The activated double bond in trans-stilbene underwent oxidative cleavage and epoxidation in parallel to give benzaldehyde and trans-stilbene oxide as the major products. The triple bond in diphenylacetylene was simply oxygenated to form benzil, together with trace amounts of ring nitration products. 1-Phenylethanol, imidazole, 2′-deoxyadenosine, and 2′-deoxyguanosine were all quite slow to react, while uracil and cytosine were almost inert to peroxynitrite. The reaction modes exhibited by peroxynitrite are too widespread and complicated to explain the whole mechanistic pathway in terms of a single active species. All reaction modes observed for the peroxynitrite to date could be classified into five categories according to their types: i) electron transfer type, ii) O-electrophilic type, iii) N-electrophilic type, iv) O-nucleophilic type, and v) radical type. Some of these may compete under certain conditions. The active species involved in each of these types of reactions are as follows: i) NO+, NO2, and OH, ii) ONOOH, iii) ONOOH and NO+, iv) OOH- and ONOO-, and v) NO2 and OH.
- Nonoyama, Nobuaki,Oshima, Hiroshi,Shoda, Chizuru,Suzuki, Hitomi
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p. 2385 - 2395
(2007/10/03)
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- Aryl, alkyl, alkenyl and alkynylmacrolides having immunosuppressive activity
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Aryl, alkyl, alkenyl and alkynyl macrolides of the general structural Formula I: STR1 have been prepared from suitable precursors by oxidation and alkylation at C-4" of the cyclohexyl ring. These macrolide immunosuppressants are useful in a mammalian host for the treatment of autoimmune diseases, infectious diseases and/or the prevention of rejection of foreign organ transplants and/or related afflictions, diseases and illnesses.
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- Benzodiazepine derivatives, compositions containing them and their use in therapy
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Compounds of formula (I), and salts and prodrugs thereof wherein: R1 represents optionally substituted C? ??alkyl or C???cycloalkyl; R2 represents an optionally substituted phenyl or pyridyl group; R3 represents C??? alkyl or halo; R? represents C??? cycloalkyl; X is 0, 1, 2 or 3; are CCK and/or gastrin antagonists. They and compositions thereof are therefore useful in therapy.
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- HELICENES : SYNTHESE PHOTOCHIMIQUE ET ETUDE RMN 19F, 13 C ET 1H DE FLUORO-1-HEXAHELICENES ET FLUORO-1-HEPTAHELICENES.
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1-Fluorohexahelicene, 1-fluoroheptahelicene and 12 substituted derivatives of these fluorohelicenes have been synthesized by the photocyclodehydrogenation of 1-fluro-11-styrylbenzophenanthrenes (Table 2) and 1-fluoro-13-styrylpentahelicenes (Table 4) respectively.The photocyclisations to heptahelicenes were accompanied in five cases, by a side reaction, namely a photodefluoration.A new synthesis of heptahelicenes is described (25-->18 : 40 percent). 1H, 19F and 13C-NMR spectra are discussed. 19F and 13C-NMR spectra of 1-fluoro-, 1-fluoro-13-methyl- and 1-fluoro-13-methoxycarbonylpentahelicene (8d, 8a and 8 R=-CO2CH3) are also included.
- Corsane, M.,Defay, N.,Martin, R. H.
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p. 215 - 232
(2007/10/02)
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