- Electrochemical and mARC-catalyzed enzymatic reduction of para-substituted benzamidoximes: Consequences for the prodrug concept "amidoximes instead of amidines"
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The mitochondrial amidoxime reducing component (mARC) activates amidoxime prodrugs by reduction to the corresponding amidine drugs. This study analyzes relationships between the chemical structure of the prodrug and its metabolic activation and compares its enzyme-mediated vs. electrochemical reduction. The enzyme kinetic parameters KM and Vmax for the N-reduction of ten para-substituted derivatives of the model compound benzamidoxime were determined by incubation with recombinant proteins and subcellular fractions from pig liver followed by quantification of the metabolites by HPLC. A clear influence of the substituents at position 4 on the chemical properties of the amidoxime function was confirmed by correlation analyses of 1H NMR chemical shifts and the redox potentials of the 4-substituted benzamidoximes with Hammett's σ. However, no clear relationship between the kinetic parameters for the enzymatic reduction and Hammett's σ or the lipophilicity could be found. It is thus concluded that these properties as well as the redox potential of the amidoxime can be largely ignored during the development of new amidoxime prodrugs, at least regarding prodrug activation.
- Bauch, Eva,Reichmann, Debora,Mendel, Ralf-Rainer,Bittner, Florian,Manke, Anne-Marie,Kurz, Philipp,Girreser, Ulrich,Havemeyer, Antje,Clement, Bernd
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- Silver-catalyzed [3+2+1] annulation of aryl amidines with benzyl isocyanide
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A silver-catalyzed [3+2+1] annulation of amidines with benzyl isocyanide toward 2,4-diaryl-1,3,5-triazines was developed. A variety of symmetrical and unsymmetrical products were obtained in moderate to good yields. This work also features an oxidant-free approach to 2,4-disubstituted triazines.
- Lu, Xiaodong,Xin, Xiaoyi,Wan, Boshun
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supporting information
p. 361 - 364
(2018/01/08)
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- TANKYRASE INHIBITORS
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The present invention relates to a compound of formula I wherein X is C(R6) or N, Y is C or N, and ring A, ring B, R1 and R2 have the meanings defined herein, provided that when ring B is carbocyclic, X is C(R6); or a pharmaceutically acceptable salt or solvate thereof. The compounds are tankyrase-1 and tankyrase-2 inhibitors and are useful in the treatment of a number of conditions, including cancer.
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Page/Page column 103
(2014/06/24)
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- Unsymmetrical 1α3-1,2,4,6-thiatriazinyls with aryl and trifluoromethyl substituents: Synthesis, crystal structures, EPR spectroscopy, and voltammetry
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A general synthetic route to 3-trifluoromethyl-5-aryl-1α3- 1,2,4,6-thiatriazinyl radicals was developed. X-ray structures were obtained for all five neutral radicals and show that they exist in the solid state as cofacial dimers linked by S...S contacts. X-ray structures were also obtained for two of the precursor chlorothiatriazines along with several aryl N-imidoylamidines, p-methoxybenzamidine, and N-chlorosulfonyl- N,N'-benzamidine. Cyclic voltammetric studies were performed on the [R2C 2N3S]. radicals in CH3CN and CH 2Cl2 with [nBu4N][PF6] as the supporting electrolyte under vacuum conditions in an all-glass electrochemical cell. The results provide quasi-reversible formal potentials for the [R2C2N3S]-/0 process in the range of -0.61 to -0.47 V, irreversible peak potentials for the [R2C 2N3S]0/+ process from 0.59 to 0.91 V at lower concentrations, and the appearance of a second, reversible oxidation process from 0.69 to 0.94 V at higher concentrations (versus the Fc0/+ couple; Fc = ferrocene). This behavior was indicative of monomer-dimer equilibrium in solution, as ascertained from digital models of the voltammograms. There is a small but measurable trend in both the oxidation and reduction potentials with varying remote aryl substituents. EPR spectra were obtained for all five neutral radicals in CH2Cl2 solutions, which confirm the concentration of the unpaired electron density on the heterocyclic core. Trends were also seen in the hyperfine splitting constants aN with varying remote aryl substituents. Calculations were performed for all three oxidation states of the [R2C2N3S]-/./+ monomeric rings; the resulting theoretical redox energies correlate well with solution phase voltammetric data.
- Boere, Rene T.,Roemmele, Tracey L.,Yu, Xin
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experimental part
p. 5123 - 5136
(2011/08/03)
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- Direct Conversion of Amidoximes to Amidines via Transfer Hydrogenation
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Amidoximes, O-alkylamidoximes, and O-acylamidoximes are directly converted to amidines by reaction with ammonium formate and Pd/C in acetic acid.
- Anbazhagan, Mariappan,Boykin, David W.,Stephens, Chad E.
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p. 2467 - 2469
(2007/10/03)
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- Reaction of arylhalodiazirines with thiophenoxide: A redox process
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Phenylbromodiazirine reacts with thiophenoxide ion in methanol to give benzonitrile, benzamidine, ammonia, and diphenyl disulfide. The reaction is general for arylhalodiazirines, with electron-withdrawing groups on the aromatic ring exerting a small rate-enhancing effect. Three potential mechanisms are suggested for this redox process. These mechanisms include an N-sulfenylated diazirine, a diazirinyl radical, and a diazirinyl anion. Ring opening of these intermediates and subsequent transformations would lead to benzonitriles, benzamidine, and ammonia. A key intermediate in these transformations is PhSNH2, 32. This intermediate has been independently generated and found to rapidly convert to ammonia and diphenyl disulfide under the reaction conditions. Another proposed intermediate, N-(phenylthio)benzamidine, 38, has also been independently generated and subjected to the reaction conditions, where benzamidine and more diphenyl disulfide result. Theoretical calculations suggest the existence of isomeric diazirinyl anions. In addition to a diazirinyl ion with charge essentially on carbon, there is also an allylic-type ion with charge on the two nitrogen atoms. Single-electron reduction of a diazirinyl radical necessarily leads to a nitrogen-centered diazirinyl anion. Conversion of this anion to the carbon-centered diazirinyl anion is a forbidden process. These theoretical studies suggest that the diazirinyl anion may be a viable intermediate in solution.
- Creary, Xavier,Sky, Anthony F.,Phillips, Gillian,Alonso, David E.
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p. 7584 - 7592
(2007/10/02)
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