- Benzothiazolyl ureas are low micromolar and uncompetitive inhibitors of 17Β-HSD10 with implications to Alzheimer’s disease treatment
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Human 17β-hydroxysteroid dehydrogenase type 10 is a multifunctional protein involved in many enzymatic and structural processes within mitochondria. This enzyme was suggested to be involved in several neurological diseases, e.g., mental retardation, Parkinson’s disease, or Alzheimer’s disease, in which it was shown to interact with the amyloid-beta peptide. We prepared approximately 60 new compounds based on a benzothiazolyl scaffold and evaluated their inhibitory ability and mechanism of action. The most potent inhibitors contained 3-chloro and 4-hydroxy substitution on the phenyl ring moiety, a small substituent at position 6 on the benzothiazole moiety, and the two moieties were connected via a urea linker (4at, 4bb, and 4bg). These compounds exhibited IC50 values of 1–2 μM and showed an uncompetitive mechanism of action with respect to the substrate, acetoacetyl-CoA. These uncompetitive benzothiazolyl inhibitors of 17β-hydroxysteroid dehydrogenase type 10 are promising compounds for potential drugs for neurodegenerative diseases that warrant further research and development.
- Aitken, Laura,Benek, Ondrej,Chribek, Matej,Dolezal, Rafael,Gunn-Moore, Frank,Hrabinova, Martina,Hroch, Lukas,Jun, Daniel,Kralova, Vendula,Kuca, Kamil,Lycka, Antonin,Musilek, Kamil,Prchal, Lukas,Schmidt, Monika,Vinklarova, Lucie,Zemanova, Lucie
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- One-Pot Protocol to Synthesize 2-Aminophenols from Anilines via Palladium-Catalyzed C-H Acetoxylation
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This paper describes a facile one-pot protocol to synthesize 2-aminophenol derivatives via a palladium-catalyzed C-H acetoxylation strategy with 5-nitropyrimidine as a directing group (DG), which can be easily preinstalled and readily removed under mild condition after the coupling. In addition, the transformation is operationally simple, has high functional group tolerance, and is amenable to gram-scale. Moreover, several examples were shown that introduction/removal of 5-nitropyrimidine and the C-H oxylation sequence could be integrated in one pot.
- Zhao, Junhao,Huang, Yifeng,Ma, Guojian,Lin, Ling,Feng, Pengju
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p. 2084 - 2091
(2019/05/21)
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- Synthesis of benzoxazoles via the copper-catalyzed hydroamination of alkynones with 2-aminophenols
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We describe herein the synthetic method to benzoxazole derivatives via the copper-catalyzed hydroamination of alkynones with 2-aminophenols. The method produced a wide variety of functionalized benzoxazole derivatives in good yields. Preliminary mechanistic experiments revealed that the reaction would proceed through the copper-catalyzed hydroamination of alkynones and the sequential intramolecular cyclization of β-iminoketones/elimination of acetophenone promoted by the copper catalyst.
- Oshimoto, Kohei,Tsuji, Hiroaki,Kawatsura, Motoi
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supporting information
p. 4225 - 4229
(2019/05/10)
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- Ortho-aminophenol derivative and preparation method thereof
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The invention first discloses a preparation method of an ortho-aminophenol derivative. The preparation method comprises the following steps: (1) by adopting an aryl amine compound as a substrate and 2-chloro-5-nitropyridine as a guiding base, reacting in acetonitrile, thus obtaining a pyridine aryl amine compound intermediate; (2) catalyzing the pyridine aryl amine compound intermediate in step (1) to make C-H activation reaction in a solvent by using iodobenzene diacetate as an oxidant and palladium acetate as a catalyst, thus obtaining an acetoxylation aniline derivative, draining, and thenperforming the chromatographic separation and purification; and (3) enabling the acetoxylation aniline derivative in step (2) to react in a tetrahydrofuran solvent for 30 min at a normal temperature by virtue of hydrazine hydrate, thus obtaining the ortho-aminophenol derivative, quenching, washing, extracting, drying, draining, and performing the chromatographic separation and purification. The invention also discloses the ortho-aminophenol derivative prepared by the method.
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Paragraph 0068; 0075; 0076; 0077; 0078; 0079
(2018/07/15)
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- Synthesis of 2-aminophenols and heterocycles by Ru-catalyzed C-H mono- and dihydroxylation
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A novel and efficient synthesis of 2-aminophenols, 2-aminobenzene-1,3- diols, and heterocycles through Ru-catalyzed C-H mono- and dihydroxylation of anilides has been developed with a new directing group strategy. The reaction demonstrates excellent reactivity, regioselectivity, good functional group tolerance, and high yields.
- Yang, Xinglin,Shan, Gang,Rao, Yu
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supporting information
p. 2334 - 2337
(2013/07/04)
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- Efficient and highly selective iron-catalyzed reduction of nitroarenes
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Pyrolysis of iron-phenanthroline complexes supported on carbon leads to highly selective catalysts for the reduction of structurally diverse nitroarenes to anilines in 90-99% yields. Excellent chemoselectivity for the nitro group reduction is demonstrated.
- Jagadeesh, Rajenahally V.,Wienhoefer, Gerrit,Westerhaus, Felix A.,Surkus, Annette-Enrica,Pohl, Marga-Martina,Junge, Henrik,Junge, Kathrin,Beller, Matthias
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supporting information; experimental part
p. 10972 - 10974
(2011/10/31)
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- The Effect of Varying Halogen Substituent Patterns on the Cytocrome P450 Catalysed Dehalogenation of 4-Halogenated Anilines to 4-Aminophenol Metabolites
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The cytochrome P450 catalysed biotransformation of 4-halogenated anilines was studied in vitro with special emphasis on the dehalogenation to 4-aminophenol metabolites. The results demonstrated that a fluorine substituent at the C4 position was more easily eliminated from the aromatic ring than a chloro-, bromo- or iodo-substituent. HPLC analysis of in vitro biotransformation patterns revealed that the dehalogenation of the C4-position was accompanied by formation of non-halogenated 4-aminophenol, without formation of NIH-shifted metabolites. Changes in the apparent Vmax for the microsomal oxidative dehalogenation appeared to correlate with the electronegativity of the halogen substituent at C4, the fluorine substituent being the one most easily eliminated. A similar decrease in the rate of dehalogenation from a fluoro- to a chloro- to a bromo- to an iodo-substituent was observed in a system with purified reconstituted cytochrome P450 IIBl, in a tertiair butyl hydroperoxide supported microsomal cytochrome P450 system as well as in a system with microperoxidase 8. This microperoxidase 8 is a haem-based mini-enzyme without a substrate binding site, capable of catalysing cytochrome P450-like reaction chemistry. Together, these results excluded the possibility that the difference in the rate of dehalogenation with a varying C4-halogen substituent arose from a change in the contribution of cytochrome P450 enzymes involved in oxidative dehalogenation with a change in the halogen substituent. Rather, they strongly suggested that the difference was indeed due to an intrinsic electronic parameter of the various C4 halogenated anilines dependent on the type of halogen substituent. Additional in vitro experiments with polyfluorinated anilines demonstrated that elimination of the C4-fluorine substituent became more difficult upon the introduction of additional electron withdrawing fluorine substituents in the aniline-ring. 19F-NMR analysis of the metabolite patterns showed that the observed decrease in 4-aminophenol formation was accompanied by a metabolic switch to 2-aminophenols and N-hydroxyanilines, while products resulting from NIH-type mechanisms were not observed. For a C4-chloro-, bromo-, or iodo-substituted 2-fluoroaniline the Vmax for the oxidative dehalogenation was reduced by the additional electron withdrawing fluorine substituent at the C2 position in a similar way. In conclusion, the results of the present study strongly indicate that the possibilities for cytochrome P450 mediated dehalogenation of 4-halogenated anilines to 4-aminophenol metabolites are dependent on: (i) the characteristics of the halogen that has to be eliminated, the most electronegative and smallest ...
- Cnubben, Nicole H. P.,Vervoort, Jacques,Boersma, Marelle G.,Rietjens, Ivonne M. C. M.
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p. 1235 - 1248
(2007/10/03)
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- Involvement of Free Nitrenium Ions, Ion Pairs, and Preassociation Trapping in the Reactions of Ester Derivatives of N-Arylhydroxylamines and N-Arylhydroxamic Acids in Aqueous Solution
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Rate and product yield data for the decomposition of the ester derivatives of N-arylhydroxylamines and N-arylhydroxamic acids 1a-i in aqueous solution in the presence of N3- support a mechanistic scheme (Scheme 5) in which the trapping by N3- changes from trapping of the free ion, to trapping of an ion pair, to a preassociation process as the ion becomes more reactive.When the rate constant for trapping of the free ion by solvent, ks, 8 s-1, trapping by both N3- and solvent occurs almost exclusively at the free ion.When 108 s-1 s 10 s-1, a change in the mechanism occurs, and trapping of the ion pair by both solvent and N3- becomes important.In this range of reactivity there is also evidence, based on the apparent magnitude of kaz', the rate constant for N3- trapping of the ion pair, that some of the reaction with N3- occurs through a preassociation process.When ks > ca. 1010 s-1 essentially all of the observed N3- trapping occurs by a preassociation process because N3-, which cannot react with the ion pair faster than the diffusion limit, can no longer compete with solvent for the ion pair.This progression in trapping mechanisms as the ion becomes more reactive with solvent is apparently an important factor in determining the carcinogenic potential of aromatic amines and amides which are metabolized into sulfuric and carboxylic acid esters of N-arylhydroxylamines and N-arylhydroxamic acids.Nitrenium ions which undergo slow reactions with solvent are selectively trapped by biologically relevant nucleophiles such as 2'-deoxyguanosine.As the rate constant for reaction with solvent increases, the nitrenium ion is no longer capable of undergoing selective trapping by nonsolvent nucleophiles because these reactions are limited by diffusion, but solvent trapping is not.
- Novak, Michael,Kahley, Mary Jo,Lin, Jing,Kennedy, Sonya A.,James, Tishia G.
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p. 8294 - 8304
(2007/10/03)
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- Acid-catalyzed amino-migration of O-phenylhydroxylamines
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The mechanism of amino-migration of O-phenylhydroxylamine (1a) was studied. It was found that 1 rearranges to give 2-aminophenol (50%) and 4-aminophenol (7%) in trifluoroacetic acid (TFA). The predominance of the ortho rearrangement of 1 clearly distinguishes this process from the Bamberger rearrangement. From cross-coupling experiments employing stable isotopes, it was clarified that the ortho rearrangement proceeds intramolecularly and the para rearrangement involves both intra- and intermolecular processes. Good first-order kinetics were obtained for the rearrangement. The Hammett plot (σ+) with a large negative slope (ρ = -7.8) indicates that initial heterolytic N-O bond cleavage of 1 occurs and generates a positive charge on the oxygen atom with considerable delocalization into the aromatic ring. An ion-molecule pair involving a phenoxenium ion and an ammonia molecule as an intermediate rationalizes all of the results. In this pair, intramolecular combination to the ortho position proceeds preferentially over that to the para position. Formation of catechol and hydroquinone can be explained in terms of nucleophilic attack of TFA on the phenoxenium ion in a solvent-separated pair.
- Haga, Naoki,Endo, Yasuyuki,Kataoka, Ken-Ichiro,Yamaguchi, Kentaro,Shudo, Koichi
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p. 9795 - 9806
(2007/10/02)
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- Hydrolysis and Fe2+-induced Reduction of N-Aryl -O-pivaloylhydroxylamines: Aqueous Solution Chemistry of Model Carcinogens.
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The N-aryl-O-pivaloylhydroxylamines, 1a-d, which serve as models for the carcinogenic metabolites of aromatic amines, decompose in aqueous media by heterolysis of the N-O bond.Substituent effects on rates of reaction and products of the decomposition of 1a-c are entirely consistent with the intermediacy of a singlet nitrenium ion.The least reactive compound in the series N-(4-nitrophenyl)-O-pivaloylhydroxylamine (1d) yields 4-nitroaniline (2d) as its major decomposition product.This material may be formed through H radical abstraction by a triplet ion, but a nitrene reaction appears to be more likely.In the presence of Fe2+ 1a-d undergo rapid reduction to the corresponding anilines 2a-d.This reaction requires complexation of the ester with Fe2+ and proceeds with heterolysis of the N-O bond since nearly quantitative yields of pivalic acid are isolated.The radical cations 25a-d appear to be the most likely precursors to the reduction products.
- Novak, Michael,Lagerman, Robert K.
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p. 4762 - 4769
(2007/10/02)
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- Hydroxamic Acid Production and Active-site Induced Bamberger Rearrangement from the Action of α-Ketoglutarate Dehydrogenase on 4-Chloronitrosobensene
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THe α-ketoglutarate dehydrogenase complex obtained from E. coli has been found to convert 4-chloronitrosobenzene (3) into N-(4-chlorophenyl)succinohydroxamic acid (4) and N-(4-chloro-2-hydroxyphenyl)succinamic acid (5).The conversion of 4-chloronitrosobenzene (3) into these two products is not quantitative and attempts to identify other, significant low-molecular-weight metabolites have been unsuccessful.Partial enzyme-inactivation has been observed during the incubation of 4-chloronitrosobensene (3) with α-ketoglutarate dehydrogenase.The direct enzymic conversion of the hydroxamic acid (4) into the isomeric product (5) did not occur.These results are interpreted on the basis of a mechanism in which N-(4-chlorophenyl)hydroxylamine (6) is generated at the enzyme active-site by a redox process.Condensation of the active-site bound products would give rise to the hydroxamic acid (4) directly, while a Bamberger-like rearrangement of the active-site bound hydroxylamine(6), followed by condensation of the resulting o-aminophenol, would explain the production of the succinamic acid.
- Corbett, Michael D.,Corbett, Bernadette R.,Doerge, Daniel R.
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p. 345 - 350
(2007/10/02)
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