1,721,128 research outputs found
Choline Chloride-Based DES as Solvents/Catalysts/Chemical Donors in Pharmaceutical Synthesis
Full text linkDES are mixtures of two or more compounds, able to form liquids upon mixing, with lower freezing points when compared to the individual constituents (eutectic mixtures). This attitude is due to the specific hydrogen-bond interactions network between the components of the mixture. A notable characteristic of DES is the possibility to develop tailor-made mixtures by changing the components ratios or a limited water dilution, for special applications, making them attractive for pharmaceutical purposes. In this review, we focused our attention on application of ChCl-based DES in the synthesis of pharmaceutical compounds. In this context, these eutectic mixtures can be used as solvents, solvents/catalysts, or as chemical donors and we explored some representative examples in recent literature of such applications
Novel approaches for using dehydrogenases and ene-reductases for organic synthesis
No full textOxidation of alcohols is a reaction of major interest for organic chemistry. However, the most common chemical routes developed so far involve the use of toxic or hazardous reagents or catalysts that often lack good chemoselectivity. In this respect, alcohol dehydrogenases (ADHs) represent a very valuable biocatalytic alternative, as they can operate in more sustainable conditions and with excellent selectivities. Another interesting class of oxidoreductases that catalyse the reduction of activated C¬C double bonds are the ene-reductases (ERs). Similarly to alcohol dehydrogenases, these are NAD(P)-dependent enzymes which do not have an actual chemical catalyst counterpart. For both enzyme groups one of the major hurdles en route to preparative applications is the need of nicotinamide cofactors. The most popular approach to tackle the cofactor-dependency issue is the use of regeneration systems able to catalyse the in situ recycling of NAD(P). Recently also increasing attention has been devoted to the use of NAD(P)-like molecules that potentially able to mimic the coenzymic activity of the native cofactor. This thesis is focused on the development of NAD(P)+ regeneration systems for ADH-catalysed oxidations and on evaluation of electron donors others than the NADPH to be applied for the ene-reductases catalysis. Chapter 1 gives an introduction on the potential and limitations of both ADHs-catalysed oxidations and ERs-catalysed reductions. As a major focus the cofactor dependency issue in these enzymes is being addressed: in the case of alcohol oxidations, the use of regeneration systems for the NAD(P)+ is discussed; the application of various reductants, including NAD(P)H-like structures, to promote ERs-catalysed reductions is also reviewed. In Chapter 2 a novel NAD(P)+ regeneration system based on the use of photoexcited flavins is presented. The scope of this work was to develop a catalytic system able to regenerate both NAD+ and NADP+, thereby being able to promote alcohol dehydrogenases-catalysed oxidations. Irradiation of flavins with visible light resulted in a dramatic rate acceleration of the NAD(P)H oxidation. The system was used to promote some model oxidation reactions by the horse liver and the Thermus sp.ATN1 enzymes. In Chapter 3, the further exploitation of the ADH from Thermus sp. ATN1 (TADH) in combination with the Thermus scodoductus ER to setup a catalytic sequence for the isomerisation of allylic alcohols into saturated ketones is described. The system was developed with a model substrate and proved to be suitable for the production of enantiopure ketones from the corresponding unsaturated alcohols. The cofactor regeneration is accomplished here by means of an enzyme-coupled approach. The crystal structure of TADH is reported and analysed with particular respect to the interaction with the ([Cp*Rh(bpy)(H2O)]2+) catalyst for the regeneration of NADH, in Chapter 5. A first basis towards understanding of the mechanisms leading to inactivation of the both enzyme and Rh-complex is discusses in here. Also structural features of this enzyme compared to other thermostable ADHs are highlighted. In Chapter 6 the use of ethylendiaminetetraacetic acid (EDTA) to promote ene-reductases catalysis upon illumination has been investigated and is reported together with the biochemical characterisation of two recently identified reductases. The Deinococcus radiodurans and the Ralstonia metallidurans enzymes have been characterised with respect to the substrate scope and cofactor preference. In Chapter 4 the use of synthetic nicotinamide analogs for the ene-reductases catalysis is reported. The investigated molecules proved to perform in the catalytic cycle just as good as the NADH. Additionally, a chemoselectivity advantage could be gained from the use of NADH analogs in the presence of contaminating ADHs. Overall this work dealt with the applicability of alcohol dehydrogenase and ene-reductases for biocatalytic applications. In ADHs catalysis the cofactor issue was addressed both by developing a novel regeneration system and by applying the concept of an enzyme coupled regeneration. On the other hand, in ERs catalysis the regeneration of the prosthetic group was tackled by the use of NADH or its synthetic analogs as reductants. A light-driven system was also used to promote the ER-reductions. Finally, the combination of an ER with an ADH for the isomerisation of allylic alcohols was developed which resulted in the setup of a promising new route for the production of saturated carbonyl compounds.BiotechnologyApplied Science
Novel approaches for biocatalytic oxyfunctionalization reactions
No full textBiocatalytic oxyfunctionalizations, especially of non - activated hydrocarbons, attract considerable attention for synthetic organic chemistry thanks to their high chemo-, regio-, and stereoselectivity, which difficult to achieve by chemical means. Many enzymatic oxyfunctionalizations have been described. However, there are many hurdles towards large scale applications, such as low activity and stability of enzymes, substrate toxicity, overoxidation, oxygen mass transfer, etc. Therefore, the aim of this thesis is to setup robust and scalable biocatalytic oxyfunctionalizations. Chapter 1 gives a general introduction on enzymatic C-H oxyfunctionalizations highlighting the great potential of heme - iron peroxygenases. Peroxygenases do not rely on expensive NAD(P)H cofactors and catalyze a variety of useful synthetic transformations utilizing H2O2 as an oxidant. However, the practical applicability of heme - peroxygenases is limited by their low stability towards H2O2. To avoid the inactivation of the enzymes, we have developed two alternative catalytic approaches for the controlled in situ H2O2 generation from O2. General applicability of the proposed methods has been demonstrated for various peroxygenase - based biotransformations in Chapters 2, 3, 4. Thus, in Chapter 2 a photocatalytic approach for in situ H2O2 generation has been applied for the CPO (chloroperoxidase from Caldariomyces fumago) catalyzed thioanisole sulfoxidation. The enzyme stability has been drastically improved; however, the productivity of the system was severely limited by low solubility and evaporation of the substrate. Therefore, the photocatalytic approach was demonstrated at preparative - scale using a surfactant - stabilized two – liquid phase system (2 LPS). Both, initial rate and robustness of the system could be enhanced significantly leading to an increase of the final product concentration by more than one order of magnitude in comparison with monophasic set - up. In Chapter 3 the proposed photocatalytic in situ generation of H2O2 proved to be a suitable approach for AaeAPO (Agrocybe aegerita aromatic peroxygenase) catalyzed epoxidation and hydroxylation reactions. High productivities and excellent enantiomeric excesses (>97%) were obtained with a broad range of substrates. Furthermore, preliminary results indicate that hundreds of thousands of turnovers can be achieved after reaction engineering, demonstrating the high potential of AaeAPO for oxyfunctionalization catalysis. In Chapter 4 an alternative in situ H2O2 generation method has been developed using a synthetic nicotinamide cofactor mimic and flavin. This method has been applied for the specific ?- or ?-hydroxylation of fatty acid catalyzed by the cytochrome P450 peroxygenases. The cytochrome P450 peroxygenases P450bs? from Bacillus subtilis and P450cl? from Clostridium acetobutylicum belong to a unique group of P450s which consume H2O2 and therefore do not require additional electron transfer proteins and NAD(P)H cofactor. Using the new method for in situ H2O2 generation the final productivity of P450 peroxygenases could be enhanced due to higher enzyme stability under operation conditions. In addition to peroxygenases, various oxyfunctionalizations can be performed by oxygenases. However, the application of isolated oxygenases, relies on efficient cofactor regeneration techniques. Formate dehydrogenase (FDH) is widely applied for NAD(P)H regeneration. However, classical FDH -based reaction systems are limited to mainly aqueous media, wherein the majority of substrates are poorly soluble. In order to circumvent this limitation we propose in Chapter 6 using formic acid esters as ‘hydrophobized’ formic acid equivalents, which simultaneously can serve as an organic phase in 2LPS reaction and as source of reducing equivalents. The concept was demonstrated using 2-hydroxybiphenyl-3-monooxygenase (HbpA)-catalyzed specific ortho-hydroxylation of phenols as model reaction. In addition, chemical methods for NAD(P)H regeneration have been employed as an alternative to enzymatic methods. The organometallic compound [Cp*Rh(bpy)(H2O)]2+ has emerged as a catalyst of choice. However, the mutual inactivation between [Cp*Rh(bpy)(H2O)]2+ and enzymes is usually encountered. To overcome this issue, in Chapter 5, we propose using artificial transfer hydrogenases (ATHs) wherein the biotin - coordinated transition metal complex is sterically shielded by complexation with streptavidin. Thereby, the mutual inactivation of the regeneration catalysts and the production enzyme(s) can be efficiently circumvented. The applicability of the concept was illustrated by combining the ATHase with HbpA, demonstrating that the general catalytic properties of ATHase and enzyme are preserved. In conclusion, this thesis addresses some major challenges of oxyfunctionalization catalysis including enzyme stability, cofactor dependency and substrate supply. The proposed methods to overcome these issues have been implemented to various enzymatic oxyfunctionalizations. Furthermore, their practical applicability has been demonstrated at preparative - scale using a two liquid phase approach. Promising results in terms of productivity and selectivity have been obtained, thereby paving the way to preparative biocatalytic oxyfunctionalization. Nevertheless, further studies, e.g. combining enzyme immobilization techniques with reaction and process engineering, are needed to substantiate the full potential of biocatalytic oxyfunctionalizations.BiotechnologyApplied Science
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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