- Catalytic Alkylation Using a Cyclic S-Adenosylmethionine Regeneration System
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S-Adenosylmethionine-dependent methyltransferases are versatile tools for the specific alkylation of many compounds, such as pharmaceuticals, but their biocatalytic application is severely limited owing to the lack of a cofactor regeneration system. We report a biomimetic, polyphosphate-based, cyclic cascade for methyltransferases. In addition to the substrate to be methylated, only methionine and polyphosphate have to be added in stoichiometric amounts. The system acts catalytically with respect to the cofactor precursor adenosine in methylation and ethylation reactions of selected substrates, as shown by HPLC analysis. Furthermore, 1H and 13C NMR measurements were performed to unequivocally identify methionine as the methyl donor and to gain insight into the selectivity of the reactions. This system constitutes a vital stage in the development of economical and environmentally friendly applications of methyltransferases.
- Mordhorst, Silja,Siegrist, Jutta,Müller, Michael,Richter, Michael,Andexer, Jennifer N.
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- Specific Residues Expand the Substrate Scope and Enhance the Regioselectivity of a Plant O-Methyltransferase
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An isoeugenol 4-O-methyltransferase (IeOMT), isolated from the plant Clarkia breweri, can be engineered to a caffeic acid 3-O-methyltransferase (CaOMT) by replacing three consecutive residues. Here we further investigated functions of these residues by constructing the triple mutant T133M/A134N/T135Q as well as single mutants of each residue. Phenolics with different chain lengths and different functional groups were investigated. The variant T133M improves the enzymatic activities against all tested substrates by providing beneficial interactions to residues which directly interact with the substrate. Mutant A134N significantly enhanced the regioselectivity. It is meta-selective or even specific against most of the tested substrates but para-specific towards 3,4-dihydroxybenzoic acid. The triple mutant T133M/A134N/T135Q benefits from these two mutations, which not only expand the substrate scope but also enhance the regioselectivity of IeOMT. On the basis of our work, regiospecific methylated phenolics can be produced in high purity by different IeOMT variants.
- Tang, Qingyun,Bornscheuer, Uwe T.,Pavlidis, Ioannis V.
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- Recyclable Hypervalent-Iodine-Mediated Dehydrogenative α,β′-Bifunctionalization of β-Keto Esters under Metal-Free Conditions
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We have developed a method for recyclable hypervalent-iodine-mediated direct dehydrogenative α,β′- bifunctionalization of β-ketoesters and β-diketones under metal-free conditions, which affords a straightforward way to synthesize benzo-fused 2,3-dihydrofurans. This efficient, mild method, which has a wide substrate scope and good functional-group tolerance, was used for the multistep synthesis of the protected aglycone of a naturally occurring phenolic glycoside. A mechanism involving Michael addition to an enone intermediate and subsequent oxidative cyclization is proposed.
- Duan, Ya-Nan,Cui, Li-Qian,Zuo, Lin-Hong,Zhang, Chi
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- Degradation of neohesperidin dihydrochalcone by human intestinal bacteria
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The degradation of neohesperidin dihydrochalcone by human intestinal microbiota was studied in vitro. Human fecal slurries converted neohesperidin dihydrochalcone anoxically to 3-(3-hydroxy-4-methoxyphenyl)propionic acid or 3-(3,4-dihydroxyphenyl)propionic acid. Two transient intermediates were identified as hesperetin dihydrochalcone 4′-β-D-glucoside and hesperetin dihydrochalcone. These metabolites suggest that neohesperidin dihydrochalcone is first deglycosylated to hesperetin dihydrochalcone 4′-β-D-glucoside and subsequently to the aglycon hesperetin dihydrochalcone. The latter is hydrolyzed to the corresponding 3-(3-hydroxy-4-methoxyphenyl)propionic acid and probably phloroglucinol. Eubacterium ramulus and Clostridium orbiscindens were not capable of converting neohesperidin dihydrochalcone. However, hesperetin dihydrochalcone 4′-β-D-glucoside was converted by E. ramulus to hesperetin dihydrochalcone and further to 3-(3-hydroxy-4-methoxyphenyl)propionic acid, but not by C. orbiscindens. In contrast, hesperetin dihydrochalcone was cleaved to 3-(3-hydroxy-4-methoxyphenyl)propionic acid by both species. The latter reaction was shown to be catalyzed by the phloretin hydrolase from E. ramulus.
- Braune, Annett,Engst, Wolfram,Blaut, Michael
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- A biocompatible alkene hydrogenation merges organic synthesis with microbial metabolism
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Organic chemists and metabolic engineers use orthogonal technologies to construct essential small molecules such as pharmaceuticals and commodity chemicals. While chemists have leveraged the unique capabilities of biological catalysts for small-molecule production, metabolic engineers have not likewise integrated reactions from organic synthesis with the metabolism of living organisms. Reported herein is a method for alkene hydrogenation which utilizes a palladium catalyst and hydrogen gas generated directly by a living microorganism. This biocompatible transformation, which requires both catalyst and microbe, and can be used on a preparative scale, represents a new strategy for chemical synthesis that combines organic chemistry and metabolic engineering. Reduction to practice: A hydrogenation reaction has been developed that employs hydrogen generated in situ by a microorganism and a biocompatible palladium catalyst to reduce alkenes on a synthetically useful scale. This type of transformation, which directly combines tools from organic chemistry with the metabolism of a living organism for small-molecule production, represents a new strategy for chemical synthesis.
- Sirasani, Gopal,Tong, Liuchuan,Balskus, Emily P.
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supporting information
p. 7785 - 7788
(2014/08/05)
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- Optical control of TRPV1 channels
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Controlling pain with light: TRPV1 channels mediate the response to noxious heat and can be activated by capsaicin, the major ingredient of chili pepper. Novel azobenzene photoswitches can be used for the optical control of TRPV1. One of these compounds antagonizes capsaicin in a light-dependent fashion, demonstrating that a photoswitchable antagonist and an agonist can be applied in concert to modulate ion channel activity. Copyright
- Stein, Marco,Breit, Andreas,Fehrentz, Timm,Gudermann, Thomas,Trauner, Dirk
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p. 9845 - 9848
(2013/09/23)
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- Synthesis of tripeptide mimetics based on dihydroquinolinone and benzoxazinone scaffolds
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In the image: The design and synthesis of peptidomimetics that maintain the configuration of the triad Asp-Thr-Gly found in the catalytic site of the HIV-1 protease (see scheme) are described. By using regioselective nitration and reductive lactamisation,
- Dantas De Araujo, Aline,Christensen, Caspar,Buchardt, Jens,Kent, Stephen B. H.,Alewood, Paul F.
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supporting information; experimental part
p. 13983 - 13986
(2012/01/06)
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- First synthesis, characterization, and evidence for the presence of hydroxycinnamic acid sulfate and glucuronide conjugates in human biological fluids as a result of coffee consumption
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A systematic investigation of the human metabolism of hydroxycinnamic acid conjugates was carried out. A set of 24 potential human metabolites of coffee polyphenols has been chemically prepared, and used as analytical standards for unequivocal identifications. These included glucuronide conjugates and sulfate esters of caffeic, ferulic, isoferulic, m-coumaric and p-coumaric acids as well as their dihydro derivatives. A particular focus has been made on caffeic and 3,4-dihydroxyphenylpropionic acid derivatives, especially the sulfate conjugates, for which regioselective preparation was particularly challenging, and have so far never been identified as human metabolites. Ten out of the 24 synthesized conjugates have been identified in human plasma and/or urine after coffee consumption. A number of these conjugates were synthesized, characterized and detected as hydroxycinnamic acid metabolites for the first time. This was the case of dihydroisoferulic acid 3′-O-glucuronide, caffeic acid 3′-sulfate, as well as the sulfate and glucuronide derivatives of 3,4-dihydroxyphenylpropionic acid.
- Fumeaux, Rene,Menozzi-Smarrito, Candice,Stalmach, Angelique,Munari, Caroline,Kraehenbuehl, Karin,Steiling, Heike,Crozier, Alan,Williamson, Gary,Barron, Denis
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supporting information; experimental part
p. 5199 - 5211
(2010/12/25)
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- Tyrosinase inhibitory activities of cinnamic acid analogues
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The aim of this study was to show how tyrosinase inhibitory activity is correlated with the structure of cinnamic acid derivatives. We synthesized cinnamic acid derivatives, and investigated their tyrosinase inhibitory and DPPH radical scavenging activities. The results show that reduction of C=C double bonds and the substituent group of cinnamic acid derivatives have an effect on antioxidant activity and tyrosinase inhibitory activity. Among these compounds, compounds 2, 6 and 6a showed a potent tyrosinase inhibitory activity with IC50 (50% inhibitory concentration) values of 115.6 μM, 114.9 μM and 195.7 μM, respectively. The results obtained provide a useful clue for the design and development of new tyrosinase inhibitors.
- Takahashi,Miyazawa, Mitsuo
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experimental part
p. 913 - 918
(2011/08/06)
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- Antineoplastic agents. 565. Synthesis of combretastatin D-2 phosphate and dihydro-combretastatin D-2
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A modified synthetic route to combretastatin D-2 (5) was devised in order to further evaluate its biological activity, for its conversion to phosphate prodrugs (25-28), and as a route to obtaining dihydro-combretastatin D-2 (42). A parallel first total synthesis of dihydro-combretastatin D-2 was completed, proceeding from a saturated 3-phenylpropionic ester intermediate via the Ullmann biaryl ether reaction (39-41). In contrast to the cancer cell growth inhibitory activity exhibited by combretastatin D-2, relatively minor structural modifications (41, 42) caused elimination of those properties.
- Pettit, George R.,Quistorf, Peter D.,Fry, Jeremy A.,Herald, Delbert L.,Hamel, Ernest,Chapuis, Jean-Charles
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experimental part
p. 876 - 883
(2009/12/26)
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- ISOQUINOLINE AMINOPYRAZOLE DERIVATIVES, THEIR MANUFACTURE AND USE AS PHARMACEUTICAL AGENTS FOR THE TREATMENT OF CANCER
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Objects of the present invention are the compounds of formula (I) their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture, as well as the use of the above-mentioned compounds in the control or prevention of illnesses such as cancer.
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Page/Page column 246
(2008/06/13)
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- Crystals of aspartame derivative
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N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester useful as a sweetener with a high potency of sweetness, is provided in the crystalline form having a high stability and a good purity which is favorable as a commercia
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- 8,9-Methylenedioxybenzo[i]phenanthridines: Topoisomerase I-targeting activity and cytotoxicity
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Substituted benzo[i]phenanthridines that have incorporated within their structure an 8,9-methylenedioxy group can exhibit topoisomerase I-targeting activity. Structure-activity studies were performed to examine the influence of saturation at the 11,12-positions of several substituted 8,9-methylenedioxybenzo[i]phenanthridines. The activities of these dihydro analogues were compared to those of their unsaturated analogues. In addition, the influence of varying substituents at the 2- and 3-positions within the A-ring of these 8,9-methylenedioxybenzo[i]phenanthridines on their relative potency as topoisomerase I-targeting agents and cell proliferation as determined using the MTT assay was investigated. 2,3-Dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine and its 11,12-dihydro derivative were among the more potent analogues evaluated with regard to topoisomerase I-targeting activity and cytotoxicity.
- Li, Dajie,Zhao, Baoping,Sim, Sai-Peng,Li, Tsai-Kun,Liu, Angela,Liu, Leroy F.,LaVoie, Edmond J.
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p. 3795 - 3805
(2007/10/03)
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- Process for production of aspartyl dipeptide ester derivative, novel production intermediate therefor, and process for production thereof
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The present invention relates to a method of manufacturing aspartyl dipeptide ester compounds, which can be used as sweeteners, and aldehydes that can be used in the manufacturing processes.
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- A facile and practical synthesis of capsazepine, a vanilloid receptor antagonist
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A facile and practical synthesis of capsazepine, a vanilloid receptor antagonist, has been accomplished from isovanillin in 8 steps via an efficient intramolecular Mannich cyclization.
- Lee, Jeewoo,Lee, Jiyoun
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p. 4127 - 4140
(2007/10/03)
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- A Formal Total Synthesis of the ACE Inhibitor K-13. An Application of Arene-Ruthenium Chemistry to Complex Chemical Synthesis
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Stoichiometric ruthenium activation of 4-chlorophenylalanine derivatives toward nucleophilic substitution, using phenoxide nucleophiles that are derived from protected dipeptides, allowed the formation of isodityrosine derivatives that are synthetic precursors to the ACE inhibitor K-13.An evaluation of carboxyl blocking groups revealed that a 2-bromoethyl ester is the most useful in terms of its compatibility with ruthenium complexation and subsequent nucleophile addition but that its removal is problematic.Conversion to iodoethyl ester using Finkelstein reaction conditions, in the presence of the peptide and amino acid functionality, provided a solution to this problem, since the iodoethyl group was easily removed on treatment with samarium diiodide.
- Pearson, Anthony J.,Lee, Kieseung
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p. 2304 - 2313
(2007/10/02)
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