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Caron, Gaétan. "Synthesis of cyclitol-based glucosidase inhibitors." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/27852.
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The first conduritol aziridine (1,2-dideoxy-1,2-epimino-myo-inositol, 1) was synthesized in seven steps from myo-inositol (2) and inhibits pABG5 β-glucosidase and yeast ⍺-glucosidase irreversibly. 1,2-0-Cyclohexylidene-myo-inositol (3) was obtained by reaction of 2 with cyclohexanone. Benzylation of 3 followed by hydrolysis of the ketal gave l,4,5,6-tetra-0-benzyl-myo-inositol (5). The two free hydroxyl groups in 5 were methanesulfonylated and the axial mesyl group in l,4,5,6-tetra-0-benzyl-2,3-di-0-methanesulfonyl-myo-inositol (12) was selectively displaced by an azido group. The resulting 1-azido-2,3,4,5-tetxa-0-benzyl-1-deoxy-6-0-methanesulfonyl-scyllo-inositol (13) was hydrogenated in the presence of HC1 to give 1-amino-1-deoxy-2-0-methanesulfonyl-scyllo-inositol (24) hydrochloride. Cyclisation of 24 under basic aqueous conditions yielded
DL-1. [Formula Omitted] The dissociation constant Ki and the inactivation rate constant ki for inactivation of pABG5 β-glucosidase by 1 were calculated to be 3.0 mM and 0.077 min⁻¹ respectively. For yeast ⍺-glucosidase inactivation, values of Ki, and ki were found to be 9.5 mM and 0.39 min-1 respectively. Finally, 24 and 31 were tested as reversible (non-covalent) inhibitors of both the glucosidases and the respective inhibition constants (Ki) determined.Science, Faculty of
Chemistry, Department of
Graduate
2
Meloncelli, Peter J. "The synthesis of several azasugars, glycosylated azasugars and disaccharides of biological interest." University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2007. http://theses.library.uwa.edu.au/adt-WU2007.0052.
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[Truncated abstract] The development of several carbohydrate-based pharmaceuticals has stimulated an increased interest in the field of carbohydrate chemistry. The discovery of Acarbose and invention of Miglitol, treatments for type II diabetes, as well as the influenza treatments, Relenza and Tamiflu, have been largely responsible for this increased interest. These treatments operate by the inhibition of glycoside hydrolases, a group of enzymes important in a variety of biological processes. This thesis involves the study of a group of glycoside hydrolase inhibitors known as azasugars, which are nitrogen-containing sugar mimics . . . The final chapter, Chapter 4, focuses on the testing of these disaccharides as a possible alternative carbohydrate source for pre-term infants. Initially, commercially available glycoside hydrolases were used to detect any hydrolysis of the four disaccharides, with (206) exhibiting the most promising results (to provide D-glucose and D-galactose). Detailed kinetic studies were then conducted using homogenates obtained from pig intestinal mucosa. Unfortunately, the results indicated that (206) was unsuitable as an alternative carbohydrate source for pre-term infants.
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Miglioli, Francesca. "Synthesis and biological evaluation of bicyclic iminosugar derivatives as inhibitors of glycosidases." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2018. http://amslaurea.unibo.it/16676/.
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During this work, five pyrrolizidine derivatives and one isoxazolidine derivative have been synthetized in order to evaluate their biological activities towards glycosidases, related to their configurations and type of bridge functionalities between the bicyclic iminosugar moiety and the aromatic part of the molecules. The final pyrrolizidine derivatives have been synthetized through click reactions (urea forming reaction, thiourea forming reaction and CuAAC reaction) performed on a common amino-pyrrolizidine precursor. The final isoxazolidine derivative has been synthetized through a CuAAC reaction. In addition, an indolizidine scaffold was obtained through a ring-closing metathesis on a dialkenyl pyrrolidine. This bicyclic compound could be of interest as intermediate for the synthesis of indolizidine derivatives with potential as glycosidase inhibitors. Biological evaluation towards glycosidases of the final six compounds synthetized in this work revealed that all of these compounds show inhibition towards almonds’ β-glucosidase and/or jack beans’ α-mannosidase.
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Scaffidi, Adrian. "Synthetic endeavours in carbohydrates." University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2007. http://theses.library.uwa.edu.au/adt-WU2007.0114.
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The overwhelming occurrence and structural diversity of carbohydrates in Nature indicate their importance in a range of fundamental life processes. Indeed, it is this diversity that has lead to the two equally diverse groups of carbohydrate-processing enzymes, namely the glycoside hydrolases and glycosyl transferases. Thus, understanding the role of both carbohydrates and their processing enzymes in biological systems has attracted significant attention. This thesis, firstly, describes endeavours towards the synthesis of an inositol ?- amino acid, along with a series of sugar α-substituted carboxylic acid esters, utilising an extension of the modified Corey-Link reaction. The emphasis of the thesis is then shifted towards the synthesis of a putative inhibitor of a family GH26 lichenase from Clostridium thermocellum (CtLic26A). The preparation of 2-deoxy-2-fluoro-β-laminarbiosyl fluoride 1 is described, along with elaboration into oligosaccharides utilising AbgE358G glycosynthase technology. Crystallographic investigations indicated that the transition state adopted by CtLic26A is in stark contrast to that utilised by the related family GH26 mannanase from Pseudomonas cellulose (Man26A). ... Following on from this work, expanding the role of the AbgE358G glycosynthase acceptor repertoire to accommodate inositol substrates was explored, furthering the synthetic utility of this enzyme. Thus, a number of inositol acceptors bearing an aryl anchor, for example 2, were prepared and shown to be surrogates for carbohydrate acceptors. ... The thesis then describes the synthesis of an acetamide derivative of 1-epivalienamine, namely 3, a putative inhibitor of β-N-acetylglucosaminidases. Both the synthesis of 3, along with kinetic data for four β-N-acetylglucosaminidases, is reported; as well, Western blot analysis indicated no inhibition of a recombinant OGTase. ... Related to the preparation of a putative inhibitor of β-N-acetylglucosaminidases was the synthesis of a conformationally rigid carbocycle derivative of PUGNAc 4, along with two other derivatives 5 and 6. These compounds were also tested against four β-N-acetylglucosaminidases and a recombinant OGTase. ... Finally, the synthesis of a mechanism-based inhibitor of family GH3 β-Nacetylglucosaminidases, namely 2-acetamido-2-deoxy-5-fluoro-β-D-glucopyranosyl fluoride 7, is described. The incorporation of an azido moiety allows for the utilisation of 8 as an effective probe of β-N-acetylglucosaminidases. ...
5
Heightman, Tom Daniel. "O-glycosidases under scrutiny: synthesis of inhibitors and structural probes : and Synthesis of a potential DNA-binding pseudotetrasaccharide /." Zürich, 1998. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=12696.
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Carpenter, Neil M. "Studies on glycosidase inhibitors." Thesis, University of Oxford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236101.
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Namgoong, Sung Keon. "The synthesis of glycosidase inhibitors." Thesis, University of Oxford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236199.
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Ong, Quyen Binh. "An enantioselective synthesis of glycosidase inhibitors." Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314209.
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Dedola, Simone. "'Click chemistry' to synthesise potential glycosidase inhibitors." Thesis, University of East Anglia, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502211.
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In this study, "click chemistry" was used to assemble a collection of potential glycosidase inhibitors. Using different "click chemistry" conditions, 21 α-D- and β-D glucopyranosyl triazoles were synthesised and assayed as inhibitors of sweet almond β-glucosidase and yeast α-glucosidase. A set of moderately effective glycosidase inhibitors was identified. In the course of this work significant differences in the reactivity of the α- and β-glucopyranosyl azides under CuAAC conditions was noted. This matter was investigated by X-ray crystallography and, in keeping with the anomeric effect, pointed to a difference in partial charge distribution in the azide and sugar moieties. Starting from maltosyl and maltotriosyl azides another collection of 12 triazoles was synthesised and all of the libraries were assayed against starch degrading enzymes from barley. A moderate inhibitor of α-glucosidase was identified, as were several weak inhibitors of β-amylase.
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Nkansah, Peter Appah. "Syntheses of pyridylglucoconjugates as potential glycosidase inhibitors." Thesis, University of East Anglia, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368182.
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Scott, J. Newberry. "The synthesis and evaluation of iminosugars as glycosidase inhibitors." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.543038.
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Holt, Karen Elizabeth. "Asymmetric synthesis of aza-sugars using aldolase enzymes." Thesis, University of Cambridge, 1993. https://www.repository.cam.ac.uk/handle/1810/272658.
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Ranzinger, Gerlinde. "Studies towards the synthesis of photochromic azasugars as glycosidase inhibitors." Thesis, University of Nottingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311741.
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Curtis, Kim Louise. "The synthesis of azadisaccharides and aminopyrrolidines as potential glycosidase inhibitors." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/30094.
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Azadisaccharides e.g. 399 (Figure 1) are known to be potent selective inhibitors of glycosidases and thus have potential as anti-viral, anti-cancer and anti-diabetic agents. We have developed new, efficient, versatile and stereoselective routes to azadisaccharides using non-carbohydrate starting materials. Pinacol methodology has been successfully used to synthesise two (2→6) linked homoaza-O-disaccharides mimics and due to the versatility of the synthetic route, modification has enabled the synthesis of a (2→6) linked homoaza-O-trisaccharide. Complementary to this, RCM (Grubbs catalyst) and stereoselective dihydroxylation (OSO4) has been utilised in the synthesis of (1→6) linked 5-deoxy-pyrrolidine and piperidine homoaza-O- and N- disaccharides as single diastereoisomers. Preliminary biological screening of these compounds has identified 399 as a weak selective inhibitor of naringinase. Aminopyrrolidines are compounds of great chemical and biochemical interest and are versatile chiral intermediates in the synthesis of compounds of considerable therapeutic value. Three novel diastereomeric 2-hydroxymethyl-3-amino-4-hydroxylpyrrolidines have been synthesised from one key homoallylic carbamate. Using a tethered aminohydroxylation and a regio- and stereoselective intramolecular epoxide opening the novel (2S, 3S, 4R) isomer 488 and (2S, 3S, 4 S) isomer 489 (Figure 2) have been synthesised respectively. Access to a third (2S, 3R, 4R) isomer was also achieved using an unprecedented regioselective intermolecular epoxide opening. Preliminary biological screening of 488 and 489 has identified both as weak inhibitors of beta-galactosidase.
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Glawar, Andreas Felix Gregor. "Design, synthesis and biological evaluation of glycosidase inhibitors in an anti-cancer setting." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:602edf26-d9ff-4fcf-8dec-c8548f3578da.
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The aim of the work described in this thesis was to explore the synthesis of glycosidase inhibitors and to evaluate their potential as anti-cancer agents. Glycosidases catalyze the fission of glycosidic bonds and are involved in vital biological functions. With regard to their potential for anti-cancer therapy, two glycosidases were identified: α-N-acetyl-galactosaminidase and β-N-acetyl-hexosaminidase. The former has been implicated in causing immunosuppression in advanced cancer patients by negating the effect of the macrophage activating factor (MAF), while the latter is secreted by invading cancer cells and hence associated with metastasis formation. The synthetic focus was on generating piperidine and azetidine iminosugars, carbohydrate mimetics with their endocylic oxygen replaced by nitrogen. Their structural similarity to carbohydrates make iminosugars excellent inhibitors of glycosidases. Following synthesis of a pipecolic amide, its previously reported potent β-N-acetyl-hexosaminidase inhibition was confirmed. This data, along with inhibition profiles of several pyrrolidines, allowed the generation of a molecular model for predicting activity of β-N-acetyl-hexosaminidase inhibitors. The model was used to select azetidines in the D/L-ribo and D-lyxo configuration as suitable candidates to be explored in novel chemical space, leading to the first synthesis of a fully unprotected 3-hydroxy-2-carboxy-azetidine. The potent α-N-acetyl-galactosamindase inhibitor 2-acetamido-1,2-dideoxy-D-galacto-nojirimycin (DGJNAc) was successfully derivatised via N-alkylation. Important structural discoveries with regard to glycosylation of vitamin D3-binding protein, the precursor of MAF, were made using MALDI mass-spectrometry. By comparing the enzymatic and cellular inhibition of N-alkylated derivatives of DGJNAc and a pyrrolidine the following generalization on iminosugar biodistribution was found: N-butylation promotes uptake into the cell/organelles, while hydrophilic side-chains restrict cellular access. An in vitro assay evaluating cancer cell invasion was devised and β-N-acetyl-hexoamindase inhibitors were shown to retard cell migration, including with the highly metastatic breast cancer cell line MDA-MB-231. Additive effects where found when the iminosugar was combined with a protease inhibitor, suggesting potential for future combination therapy.
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Neuss, Judi. "Fragmentation-cyclisation approaches to the synthesis of aza-sugars." Thesis, University of Nottingham, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338541.
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Tanaka, Kelly Sean Eichi. "Synthesis and evaluation of novel conformationally biased and carbocyclic based glycosidase inhibitors." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0025/NQ51926.pdf.
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Brazdova, Barbora. "Synthesis and studies of carbohydrate mimetics as glycosidase inhibitors and molecular switches." Scholarly Commons, 2006. https://scholarlycommons.pacific.edu/uop_etds/2651.
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Part I . We explored the synthesis of a C -glycoside synthesis from L-fucose and malononitrile in the presence of a base catalyst. The reaction was much faster than the previously studied Henry condensation, and went further---to a double cyclization of 2:1 adduct with a novel dioxabicyclic structure. It provides a new route for the synthesis of chiral polysubstituted dihydropyrans and dihydropurans. A series of carbasugars was synthesized and tested for inhibitory activity towards fungal glycosidases from Aspergillus oryzae and Penicillium canescens . In order to reveal the dependence of inhibition on the alkyl group R, several derivatives with variable alkyl chain lengths were prepared and screened. Part II . Cyclohexane-based conformationally controlled ionophores, an emerging new class of molecular switches, provide a new and promising approach to allosteric systems with negative cooperativity. Protonation of trans -2-aminocyclohexanols was observed to cause dramatic conformational changes: due to an intramolecular hydrogen bond, a conformer with equatorial position of ammonio- and hydroxy-groups becomes predominant. This signal is mechanically transmitted by the structure of the molecule, inducing a conformational change in the second site and decreasing its affinity for an appropriate guest. Thus, these structures can serve as powerful conformational pH-triggers. The trans -2-aminocyclohexanol moiety has been used for pH-triggered conformational switching of crown ethers and podands, and their complexes with metal ions. The variation of the NR 2 group allows broad tuning of the conformational equilibrium, and thus tuning of the complexing ability of these allosteric ionophores. Heterotropic allosteric systems with high negative cooperativity may find many applications, such as membrane transport and drug delivery.
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Maxwell, Vanessa L. "Studies on ring closure heterometathesis and the synthesis of novel glycosidase inhibitors." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/29972.
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Compound I was synthesised to study intramolecular ring closing metathesis of an oxime and an olefin. In the event an intermolecular reaction took place to give II. (Fig. 11160A).;A series of bias imines IV were synthesised and also subjected to ring closure metathesis conditions using the Grubbs catalyst. No cyclisation was observed. (Fig. 11160B).;Three diamino sugar derivatives V were prepared by epoxide opening of the corresponding 2,3 manno (up) epoxide. Benzylidene deprotection was not possible. (Fig. 11160C).;A further six examples of deprotected diamino altro derivatives 395b-g were prepared and tested for glycosidase inhibition and the best results were obtained when n = 4 and n = 5 where IC50 values gave 0.15 mM and 0.63 mM respectively for beta-galactosidase from bovine liver. Nine examples of the benzylamino altro derivatives were prepared and tested for glycosidase inhibition. IC50 values obtained gave 70 microM and 90 microM where n = 3, R = H and n = 4, R = H respectively for beta-galactosidase from bovine liver. (Fig. 11160D).;Opening the manno epoxide produced seven examples and the structure of the products were proved with an X-ray structure where R = morpholine. The stereochemistries of the other examples were assigned following 13 C comparison. By contrast opening of the allo epoxide gave attack at C-3 and this fact was determined by an X-ray structure on R = furanyl. 13C comparison indicated that the other examples had followed attack at C-3.
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Heck, Marie-Pierre. "Synthese d'amidines d'interet therapeutique inhibiteurs potentiels de glycosidases a visee anti vih." Strasbourg 1, 1994. http://www.theses.fr/1994STR15033.
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Chevrier, Carine. "Synthèse et évaluation d'aminosucres, inhibiteurs de fucosidases : structure de base pour la conception d'inhibiteurs de fucosyltransférases." Mulhouse, 2003. https://www.learning-center.uha.fr/opac/resource/synthese-et-evaluation-daminosucres-inhibiteurs-de-fucosidases-structure-de-base-pour-la-conception-/BUS3681656.
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L'objectif de ce travail a été de synthétiser des analogues stables du GDP-béta-L-fucose en tant qu'inhibiteurs de fucosyltransférases (agents anti-inflammatoires potentiels). Nous avons, dans un premier temps, synthétisé des analogues de fucose de type aminosucre qui ont été évalués sur l'alpha-L-fucosidase. Dans la série la plus active, nous avons développé une nouvelle voie de synthèse d'un puissant inhibiteur de fucosidase, donnant accès à une structure de base facilement fonctionnalisable : la nitrone en série L-lyxose synthètisée à partir du D-ribose. Des groupes chélatants, acides hydroxamiques et acides phosphoniques, ont été greffés par cyclo-additions 1,3-dipolaires ou substitutions nucléophiles sur ce composé de base. Il reste nécessaire d'inverser la position pseudo-anomérique des composés obtenus. Quelques approches sont discutées. L'activité des composés a été évaluée sur l'alpha-L-fucosidase et l'alpha-(1,3)-fucosyltransférase de type IIIThe aim of this work was to synthesize stable analogs of GDP-beta-L-fucose as fucosyltransferase inhibitors (potentiel anti-inflammatory agents). Aminosugars as analogs of fucose were first synthesized ans evaluated on alpha-L-fucosidase. In the most active series, a novel synthetic route of a potent fucosidase inhibitor was developped and afforded the nitrone in L-lyxose series obtained from D-ribose and readily fonctionalizable. Chelating groups like hydroxamic acids or phosphonic acids were grafted by 1,3-dipolar cyclo-addition or via nucleophilic substitutions on this nitrone. However, the pseudo-anomeric position of our compounds has to be inverted and several methods are discussed. The activity of the compouds was evaluated on alpha-L-fucosidase and on type III alpha-(1,3)-fucosyltransferase
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Concia, Alda Lisa. "Chemoenzymatic synthesis of sugar-related polyhydroxylated compounds, iminocyclitols and their derivatives as glycosidase inhibitors." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/113239.
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Section 1 (Introduction) is a comprehensive review of the subjects discussed in this thesis: biocatalysis, aldolases and iminocyclitols. It contains a description of the application of dihydroxyacetone phosphate (DHAP) and dihydroxyacetone (DHA) utilizing aldolases to the chemoenzymatic synthesis of bioactive compounds and an introduction to the structure, biological activities and synthesis of iminocyclitols. Recent bibliographic references are included at the end of the section.
Section 2 (Objectives) outlines the aims of this thesis.
Section 3 (Results and discussion) describes the studies carried out in this thesis. Bibliographic references are included as an overview of previous results and to support our statements at the end of each chapter.
- Section 3.1 deals with the application of D-fructose-6-phosphate aldolase in organic chemistry. It describes the chemoenzymatic preparation of polyhydroxylated compounds, sugars 1-deoxy-D-xylulose and 1-deoxy-D-ido-hept-2-ulose and iminocyclitols 1-deoxynojirimycin, 1-deoxymannojirimycin and N-alkylated derivatives, 1,4-dideoxy-1,4-imino-D-arabinitol and 1,4,5-trideoxy-1,4-imino-D-arabinitol. An unprecedented methodology, having as a key step a novel enzymatic aldol addition reactions catalyzed by D-fructose-6-phosphate aldolase, is presented.
- Section 3.2 presents the cascade chemical-enzymatic synthesis of a collection of novel 1,4-dideoxy-1,4-imino-D- and -L-arabinitol (DAB and LAB) 2-aminomethyl derivatives including 2-oxopiperazine conjugates which have an interest as potential glycosidase inhibitors.
- Section 3.3 describes the chemoenzymatic synthesis of novel polyhydroxylated pyrrolizidines of the family of casuarines by means of an asymmetric strategy based on cascade aldol additions catalyzed by dihydroxyacetone phosphate (DHAP) and dihydroxyacetone (DHA) aldolases.
- Section 3.4 describes the methodology and results of the preliminary in vitro assays for glycosidases inhibition activity of some of the compounds synthetized during the course of this thesis.
Section 4 (Experimental) describes the procedure for the experimental work carried out in this project. 1H and 13C NMR spectra can be found in the attached CD.La reacción aldólica es uno de los métodos más útiles y potentes para la formación de enlaces carbono carbono que permite, simultáneamente, la funcionalización y generación de nuevos centros estereogénicos adyacentes. Las aldolasas dependientes del fosfato de dihidroxiacetona (DHAP) catalizan estereoselectivamente la adición aldólica de DHAP a una gran variedad de aldehídos aceptores y han sido objeto de numerosos estudios que demuestran su utilidad como catalizadores en síntesis orgánica asimétrica. La principal limitación de esta clase de aldolasa es su estricta especificidad por el sustrato dador, la DHAP, que es un reactivo costoso y químicamente inestable. Por ello, los estudios dirigidos a la eliminación de la necesidad de la utilización de DHAP mediante estrategias de ingeniería de reacción, evolución dirigida, o a través del descubrimiento de nuevas enzimas naturales, son de gran interés. En este contexto el descubrimiento de la D-fructosa 6-fosfato aldolasa (FSA), una enzima natural que acepta dihidroxiacetona (DHA) como dador, ha sido de enorme importancia. El objeto de esta tesis es la aplicación de aldolasas dependientes de DHA y DHAP a la síntesis de compuestos quirales bioactivos. Los iminociclitoles son una clase de glicomiméticos muy atractivos en química médica ya que poseen actividad inhibidora de glicosidasas y glicosiltransferasas y, por tanto, con un vasto potencial terapéutico para el tratamiento de enfermedades como diabetes, infecciones virales y cáncer, entre otras. En este trabajo se describe una metodología quimioenzimática para la preparación de desoxiazúcares e iminociclitoles cuyas etapas clave son nuevas adiciones aldólicas estereoselectivas de dihidroxiacetona (DHA) e hidroxiacetona (HA) a diferentes aldehídos catalizadas por FSA. Mediante esta estrategia se han obtenido los iminociclitoles 1-deoxinojirimicina, 1-deoximannojirimicina y sus derivados N-alquilados, 1,4-dideoxi-1,4-imino-D-arabinitol y 1,4,5 trideoxi-1,4-imino-D-arabinitol y los desoxiazúcares 1-deoxi-D-xilulosa y 1 deoxi-D-ido-hept-2-ulosa. El 1,4-dideoxi-1,4-imino-D-arabinitol (DAB) y su enantiómero (LAB) son pirrolidinas polihidroxiladas con una amplia actividad inhibidora de varias glicosidasas. Las pirrolizidinas polihidroxilados son una clase de iminociclitoles bicíclicos que también poseen una importante actividad biológica. En este trabajo se presenta una estrategia quimioenzimática que emplea aldolasas dependientes de DHA y DHAP, para la síntesis de DAB y LAB, de una colección de sus derivados 2-aminometílicos y conjugados 2 oxo-piperazinicos y de nuevas pirrolizidinas polihidroxiladas de la familia de las casuarinas, todos con potencial actividad inhibidora de glicosidasas.
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Camps, Bres Flora. "Synthèse d'aminocyclitols, inhibiteurs potentiels de glycosidases lysosomales, via des aldolases." Phd thesis, Université Blaise Pascal - Clermont-Ferrand II, 2010. http://tel.archives-ouvertes.fr/tel-00629666.
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Les glycosidases sont des enzymes impliquées dans de nombreux processus biologiques. Entre autres, elles sont responsables de la dégradation des déchets polysaccharidiques de nos cellules. Lorsqu'une modification génétique touche un gène qui code pour une de ces enzymes, des pathologies graves regroupées sous l'appellation de " maladies lysosomales " peuvent être déclenchées. L'objectif de ce projet a été de proposer une méthode de synthèse efficace de molécules potentiellement actives spécifiquement sur l'une ou l'autre de ces maladies. Les molécules ciblées sont des inhibiteurs de glycosidases de la famille des aminocyclitols, utilisés dans une stratégie thérapeutique émergente " par molécules chaperonnes ". La méthode de synthèse développée s'appuie sur une étape enzymatique clé utilisant les aldolases comme catalyseurs et répondant aux contraintes environnementales actuelles de la chimie verte. Nous avons atteint nos objectifs grâce à l'utilisation de trois aldolases différentes, produites et purifiées pour la première fois au sein de notre laboratoire. Il s'agit de la fuculose-1-phosphate aldolase F1PA, de la rhamnulose-1-phosphate aldolase R1PA et de la nouvellement découverte fructose-6-phosphate aldolase FSA. La formation d'une quarantaine de nitrocyclitols, de stéréochimies définies, précurseurs des aminocyclitols correspondant, a ainsi été réalisée avec de très bons rendements de synthèse.
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Best, Daniel. "Rare monosaccharides and biologically active iminosugars from carbohydrate chirons." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:028392ce-6580-4fb9-bdc3-9be702b951e4.
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Iminosugars are polyhydroxylated alkaloids, and can be viewed as sugar analogues in which the endocyclic oxygen atom has been replaced with nitrogen. These compounds are highly medically relevant and their biological activity is largely due to their inhibition of glycosidases. Several examples of the iminosugar class are currently marketed as drugs, and many more are in earlier stages of development for a variety of diseases and disorders. The most fruitful approaches to the chemical synthesis of iminosugars have utilised carbohydrate starting materials as optically pure chiral building blocks, or chirons. Most of the monosaccharides are not readily available, but the relatively few naturally abundant cheap sugars have been exploited as chirons for over a century. The availability of the rare sugars is growing with the development of a new biotechnological approach to their synthesis, known as Izumoring. This thesis is primarily concerned with the chemical synthesis of iminosugars from carbohydrate starting materials. The synthesis of unnaturally functionalised sugar polyols and their suitability as substrates for the Izumoring process is also discussed. Chapter 1 provides a brief general overview of the history, natural occurrence and therapeutic application of iminosugars. General strategies for their synthesis from carbohydrate chirons are discussed. Chapter 2 concerns divergent syntheses of several iminosugar targets from both enantiomers of glucuronolactone and their biological evaluation. A new scaleable synthesis of the natural product 1-deoxynojirimycin is presented that has since been adopted for commercial purposes, as well as an efficient strategy for the synthesis of both enantiomers of 2,5-dideoxy-2,5-imino- mannitol and their novel amino acid analogues. Access to hexosaminidase inhibiting acetamido- substituted piperidines is presented, including 2-acetamido-1,5-imino-1,2,5-trideoxy-D- galactitol, which has been found to be one of the few known potent and specific inhibitors of α- N-acetyl-galactosaminidase. This inhibitory profile may allow the compound’s use for further investigation of a strategy for cancer treatment. Chapter 3 concerns the synthesis of carbon branched pyrrolidines and their biological evaluation. A novel and highly potent α-glycosidase inhibitor has been discovered, synthesised by a strategy that utilises the benzhydryl ether as key protecting group. A mild method for the introduction of this protecting group has been shown to be general to a range of sterically congested and/or acid/base sensitive carbohydrate lactones. Chapter 4 concerns the synthesis of deoxygenated and fluorinated sugar alcohols and their successful biotechnological transformation into ketoses by the Izumoring process. Publications arising from this work are included in the Appendix.
25
Fraser, Rebecca Dawn. "Isolation of natural product inhibitors and synthesis of inhibitors of signal transduction : Part II structure-activity relationship for a series of glycosidase inhibitors." Diss., Georgia Institute of Technology, 1993. http://hdl.handle.net/1853/30508.
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Zelli, Renaud. "Synthèse sans catalyseurs métalliques de systèmes multivalents à base d'iminosucres, nouveaux inhibiteurs de glycosidases." Thesis, Montpellier, Ecole nationale supérieure de chimie, 2015. http://www.theses.fr/2015ENCM0015.
Full textAbstract:
Les iminosucres sont des composés azotés polyhydroxylés mono- (pyrrolidine, piperidine, azepane) ou bicycliques (pyrrolizidine, indolizidine, nortropane) démontrant une forte activité inhibitrice envers les glycosidases, enzymes catalysant l'hydrolyse des liaisons glycosidiques des glycoconjugués. Le développement de nouveaux dérivés d'iminosucres est essentiel afin d'obtenir de nouveaux traitements contre des maladies comme le diabète de type II, la mucoviscidose ou les troubles du stockage lysosomale (maladies de Gaucher ou de Fabry par exemple). Des études récentes ont démontré que l'utilisation de systèmes multivalents d'iminosucres peut amener à des inhibitions plus fortes et plus sélectives envers les glycosidases comparés aux inhibiteurs monovalents. Cependant, une grande majorité de ces systèmes multivalents, incluant des systèmes multivalents basés sur une plateforme de type calixarène synthétisés au début de cette thèse, sont obtenus grâce à la cyclo-addition azoture alcyne catalysée par le cuivre(CuAAC). Malheureusement, cette réaction puissante mène à la contamination des systèmes multivalents par des quantités non négligeables d'ions cuivre toxiques. C'est pour cela que le principal but de ce doctorat a été de développer de nouvelles méthodes de ligations afin de former des architectures multivalentes d'iminosucres sans utiliser de catalyseurs métalliques toxiques.Premièrement, des ligations déjà exploitées pour la préparation de sucres multivalents comme l'addition radicalaire photoinduite d'un thiol sur un alcène terminal (couplage thiol-ène) et la ligation oxime ont été appliqués aux iminosucres avec succès. Ces approches ont alors permis de synthétiser des systèmes multivalents basés respectivement sur des plateformes de type calixarènes ou peptides cycliques.Dans un second temps, une nouvelle approche vers des systèmes multivalents de sucres et d'iminosucres a été développée en exploitant les remarquables stabilité et réactivité des fluorures de sulfonyle. Le couplage de ces derniers avec des partenaires portant une amine primaire a permis d'obtenir des clusters de sucres et d'iminosucres liés par une fonction sulfonamide avec de très bons rendements.Parallèlement, le couplage thiol-ène a permis la préparation simple et rapide de pseudo-disaccharides d'iminosucres, une nouvelle classe d'inhibiteur de glycosidases exhibant de meilleures activités et sélectivités que les iminosucres monosaccharidiques correspondants. Ce comportement est probablement du à la présence de l'unité saccharidique qui améliore l'analogie entre l'inhibiteur et les oligosaccharides naturels, substrats des glycosidasesIminosugars are naturally occurring, polyhydroxylated monocyclic (pyrrolidine, piperidine, azepane) and bicyclic (pyrrolizidine, indolizidine, nortropane) nitrogenated compounds endowed with strong inhibition activity against glycosidases, the enzymes that catalyse the cleavage of the glycosidic bonds in glycoconjugates. The development of new iminosugar derivatives is essential to obtain new treatments against diseases such as type II diabetes, cystic fibrosis or lysosomal storage disorders (Gaucher and Fabry diseases). Although the development of glycosidase inhibitors based on iminosugar clusters was not explored for a long period of time, recent studies have demonstrated that multivalent iminosugars are stronger and more selective inhibitors than the corresponding monovalent compounds. However, nearly two thirds of all the di- and multivalent iminosugars known to date, including the calixarene-based iminosugar clusters synthesized at the beginning of the thesis work, were obtained by means of the copper-mediated azide-alkyne cycloaddition (CuAAC). Unfortunately, this highly efficient reaction leads to the contamination of the multivalent compounds by significant amounts of noxious copper ions. Thus, the main aim of the present PhD research was the development of new ligation tools for the synthesis of multivalent iminosugars in the absence of metal catalysts. First, the ligations already exploited for the preparation of multivalent sugars, such as the photoinduced radical addition of thiol to terminal akenes (thiol-ene coupling) and the oxime ligation, were successfully applied to the iminosugars. Both approaches allowed the synthesis of iminosugar clusters based on calixarene and cyclopeptide scaffolds, respectively. Then, an unprecedented approach to multivalent sugars and iminosugars was developed taking advantage of the uncommon stability and reactivity of the sulfonyl fluoride moieties. The coupling of the latter with partners bearing a primary amine group afforded the corresponding sulfonamide-linked sugar and iminosugar clusters in high yield. Finally, the above-mentioned thiol-ene coupling also allowed the straightforward preparation of new iminosugar pseudo-disaccharides, a class of inhibitors endowed with higher glycosidase selectivity than the corresponding monosaccharidic iminosugar. This feature is due to the presence of the sugar unit which improves the analogy with the natural oligosaccharidic substrates of the glycosidases
27
Razavi, Hossein. "Amino acid Schiff base methodology for the synthesis of glycosidase inhibitors: Polyhydroxylated pyrrolidines and indolizidines." Diss., The University of Arizona, 1999. http://hdl.handle.net/10150/284049.
Full textAbstract:
The concise enantioselective syntheses of iminolyxitol and iminoribitol glycosidase inhibitors starting from benzophenone imines, of D-serine and L-alanine esters are presented. The reductive alkenylation of the Schiff bases followed by substrate-directed dihydroxylation and cyclization under various amino dehydration conditions (Ph₃P, CCl₄, or TEMPO oxidation/NaCNBH₃ reduction) gave the polyhydroxylated pyrrolidines in excellent overall yields (23% for 1 → 8a, 12% for 1 → 8b, 13% for 11 → 18a). In addition, synthesis of indolizidine glycosidase inhibitor 8- epi-swainsonine has been achieved. This approach featured trihydroxylated pyrrolidine 8a as an advanced intermediate in the synthesis of polyhydroxylated indolizidine alkaloid 25a, and highlighted efficiency in protecting group manipulation and stereocontrol in allylation with various allyltin reagents. In particular, a tandem protection-deprotection method converted pyrrolidine 8a to its corresponding partially protected analog which upon Swern oxidation and highly diastereoselective allylation afforded the required 3-carbon homologue. Subsequent hydroboration and cyclization furnished the polyhydroxylated indolizidine alkaloid in a limited number of steps and a good overall yield (29% for 8a → 25a). In a parallel sequence of reactions, pyrrolidine 8b was converted to 1,2-di-epi-swainsonine triacetate 25b in 32% overall yield.
28
MONTHILLER, SOPHIE. "Synthese de 9-oxa-quinolizidines, inhibiteurs potentiels de glycosidases a visee anti-vih." Université Louis Pasteur (Strasbourg) (1971-2008), 1994. http://www.theses.fr/1994STR13138.
Full textAbstract:
Ce travail traite de la synthese et de l'evaluation biologique de 9-oxaquinolizidines, inhibiteurs potentiels de glycosidases a visee anti-sida. La conception de ces nouveaux inhibiteurs de glycosidases possedant une fonction perhydro-oxazine, a ete realisee en se basant sur le mecanisme d'hydrolyse des glycosides. Le principe des syntheses repose sur l'utilisation d'hexopyranoses comme produit de depart, de meme stereochimie que les composes souhaites. Cette derniere a ete conservee via des reactions d'amination reductrice stereoselectives. Les reactivites observees en serie glucose, mannose et xylose tres differentes des intermediaires, ont necessite l'utilisation de sequences reactionnelles differentes et specifiques. Celles-ci nous ont conduit a developper trois nouvelles reactions: 1) une nouvelle synthese de perhydro-oxazines a partir d'hydroxylactames; 2) une synthese stereoselective de tetrahydrofuranes fonctionnalises en milieu neutre ou basique; 3) une reaction d'inversion au niveau du carbone 2 de lactones derivees du glucose et du mannose, induite par l'iodure de magnesium
29
Lenagh-Snow, Gabriel Matthew Jack. "The synthesis of azetidine and piperidine iminosugars from monosaccharides." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:207235d5-2ea5-4724-92fd-924fa0ccd4ed.
Full textAbstract:
Iminosugars are polyhydroxylated alkaloids, and can be generally defined as sugar mimetics in which the endocyclic oxygen atom has been replaced with a basic nitrogen. A common affect of this atomic substitution is to bestow these compounds with the ability to inhibit various sugarprocessing enzymes; most significantly the glycosidases (glycoside hydrolases) which areintimately involved in a huge array of biological functions. Compounds which inhibit these enzymes concordantly possess much potential as medicinal agents for the treatment of a variety of diseases. Several iminosugars have already achieved market approval as drugs, and many more are promising candidates in the late stages of clinical development. As such there remains considerable interest in this class of compound, both in terms of the exploration of novel iminosugar structures, as well as the continual development of more efficient general methodology for their synthesis. The densely-packed functionality and stereochemical information present in iminosugars makes them challenging targets for asymmetric chemical synthesis, whereas carbohydrates are clearly very attractive as chiral-pool starting materials for this purpose. Indeed, the majority of the most successful syntheses of iminosugars use the latter approach, and such is the focus of this thesis. Chapter 1 presents a relatively brief introduction to iminosugars, including their types of structure, natural occurrence and biological mode of action. The rationale behind their use as therapeutic agents for the treatment of some significant disease targets is also discussed. Chapter 2 is concerned with the preparation of a number of novel polyhydroxylated azetidines, and their evaluation as glycosidase inhibitors. Such compounds represent an almost entirely neglected class of iminosugars within the literature. An overview of natural and synthetic products incorporating an azetidine motif is given, as well as a brief review of preparative methods and known azetidine iminosugars. A highly efficient and flexible method for the key azetidine ring formation is demonstrated by the cyclisations of 3,5-di-O-triflates of pentoses and hexoses, and of a 2,4-di-O-triflate of glucose, with various primary amines. In this manner, many azetidine triols and tetrols were prepared in good yield. Furthermore, this process is readily adaptable to the installation of added functionality to the azetidine scaffold, as demonstrated by the preparation of 1-acetamido analogues. The initial biological screening of these compounds showed a promising array of glycosidase inhibition, including that of selective inhibition of fungal enzymes. Chapter 3 describes a strategy with which to prepare all sixteen stereoisomers of a known piperidine iminosugar, alpha-homonojirimycin (alpha-HNJ), in a highly divergent manner from just four of the possible thirty-two 6-azidoheptitols using traditional chemical synthesis in tandem with biotechnological transformations. One half of the execution of this strategy is described in this thesis. Two 6-azidoheptitols were prepared from D-mannose, thereby providing access to four 6-azidoketoheptoses through a combination of microbial oxidation and enzymatic epimerisation. Catalytic hydrogenation of these 6-azidoketoheptoses furnished four diastereomeric mixtures of 2,6-iminoheptitols, with varying degrees of stereoselectivity. Purification of these mixtures allowed six 2,6-iminoheptitols to be isolated, two of which have never previously been tested for glycosidase inhibition. Significantly, one of them was found to be a potent and highly selectiveinhibitor of alpha-galactosidases, and may therefore be of interest in the treatment of Fabry disease.
30
Ramstadius, Clinton. "Synthesis of Carbohydrate Mimics and Development of a Carbohydrate Epimerisation Method." Doctoral thesis, Stockholms universitet, Institutionen för organisk kemi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-45855.
Full textAbstract:
In this thesis the synthesis of several hydrolytically stable carbohydrate mimics with the potential to function as glycosidase or lectin inhibitors are described. This work is presented in Chapters 2-5. Chapters 2 and 3 describe synthetic efforts for producing carbasugars, and include the first synthesis of 1,2-bis-epi-valienamine and the preparation of two previously known aminocarbasugars. All three compounds were synthesised starting from D-mannose, using ring-closing metathesis as the key step. 1,2-Bis-epi-valienamine was found to inhibit Cellulomonas fimi β-mannosidase with a Ki value of 140 mM. Also included is the development of a novel synthetic route from cheap D-fructose to three mannose-mimicking carbasugars using a ring-closing metathesis strategy. Two of the compounds are potential inhibitors of the FimH adhesin. In Chapters 4 and 5 the synthesis of a number of pseudodisaccharides are presented; valienamine- and epi-valienamine-containing pseudodisaccharides and a small library of S-linked pseudodisaccharides were prepared. Various synthetic strategies were explored, including an alkylation strategy, Mitsunobu couplings, and sulfonate displacements. This is the first report on the synthesis of a valienamine pseudodisaccharide with β-lyxo-configuration. Two of the S-linked pseudodisaccharides were found to bind to Concanavalin A with high affinity. The final chapter (Chapter 6) of this thesis focuses on the development of a carbohydrate epimerisation method using transition metal catalysis. Two equilibrium constants involving gluco/manno- and gluco/allo-alcohols were determined via this method.At the time od doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Manuscript. Paper 5: Manuscript.
31
Roth, Alexander J. K. [Verfasser], and Christian B. W. [Akademischer Betreuer] Stark. "Untersuchungen zur Aldehyd-Hydrat-Stabilisierung durch N-Oxide sowie Synthese und Untersuchung von Morpholinderivaten als Glycosidase-Inhibitoren / Alexander J. K. Roth. Betreuer: Christian B. W. Stark." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2014. http://d-nb.info/1057002046/34.
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Wu, Pey Jiuann, and 吳佩絹. "Synthesis of glycosidase inhibitors." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/91565010674613604602.
Full textAbstract:
碩士國立彰化師範大學
化學系
96
We successfully synthesized a series of aza-C-glycoside derivatives, N-alkylated aza-C-glycosides and aza-C-disaccharides starting from the commercial D-ribose. Our strategy takes advantage of a direct coupling reaction of alkylated amine with 5-OMs-ribose and further underwent intramolecular hetero-Michael reaction under base condition. In addition, we also prepared a series of ether bridge bicyclo azasugar 58 and N-alkyl ether bridge bicyclo azasugar derivatives 60 starting from 38. When further deprotected, they may therefore provide access to a large number of variously substituted analogues of 1-deoxynojirimycin which are useful for the development of potent glycosidase inhibitors.
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GUO, Chao-Ci, and 郭朝其. "The Synthesis of glycosidase inhibitors and fluorescent chemosensors derivatives." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/58171484089769612463.
Full textAbstract:
碩士國立彰化師範大學
化學系
96
We synthesized a series of N-alkylated aza-C-glycosides starting from the commercial D-ribose. Our strategy take advantage of a direct coupling reaction of alkylated amine with 5-OMs-ribose and further undergoes intramolecular hetero-Michael reaction under base condition. In addition, we also synthesized a novel cyclodextrin-like artifical receptor which is a 1,2,3-triazole compound through Huisgen 1,3-dipolar cycloadditions of alkynes to azides. This idea is based upon the assumption that a cyclic array of carbohydrate moieties, nitrogen atom and amino acid functional groups may lead to exquisite specificity of recognition and catalysis. If compound 9、10、11 with an appropriate appended chromophore would be a good candidate for cation probes because of their aza-crown structures which can be used as a cation recognition unit.
34
Li, Heng-Yi, and 李恆毅. "Synthesis of aminocyclitols(deoxyinosamines) and polyhydroxyindolizidines for potential glycosidase inhibitors." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/67744090257103290862.
Full textAbstract:
碩士淡江大學
化學學系碩士班
95
Naturally occurring polyhydroxylated aminosugars are considered to be potential glycosidase inhibitors. These glycosidase inhibitors possess potential in the treatment of cancers, HIV, diabetes and metabolic disorders. Especially in diabetes, it is estimated that the number of diabetes patients is expectd to rise from the current estimated of 150 million to 220 million in 2010. Polyhydroxylated aminosugars have been known as glycosidase inhibitors. They display the same stereochemistry as the corresponding hexoses, exceptor nitrogen atom replacing the original oxygen. Herein we report a stereoselective synthesis of tetrahydroxylated aminocyclitols starting from D-(-)-quinic acid. Subsequent ring-closing metathesis (RCM) was employed to synthesize dihydroxylated indolizidines from trans-4-hydroxy-L-proline. The resulting tetra-hydroxylated aminocyclitols and di-hydroxylated indolizidines are glycosidase inhibitors.
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林昌慶. "Synthesis of α(2→9) Oligosialic Acids and Glycosidase Inhibitors." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/45587978576346815030.
Full textAbstract:
博士國立清華大學
化學系
94
Chapter 1: Synthesis of ��(2→9) Oligosialic Acids In the first part of this chapter, we accomplished new phosphite-based donors for efficient and highly ��-selective synthesis of oligosialic acids (up to pentasialoside) using iterative sialylation. Although the ��-selectivity decreased with increasing size of the donor, pure pentasialic acid was obtained on the 10 mg scale. We believe that these phosphite donors will have applications in the development of polysialic acid based vaccines. In the second part, we focussed on the large-scale synthesis of per-O-acetylated saccharides using LiClO4 as a catalyst and a stoichiometric amount of acetic anhydride under solvent free conditions. The peracetylated saccharides smoothly underwent bromination and thioglycosidation in the one-pot synthesis manner to yield synthetically valuable building blocks. Chapter 2: Synthesis of Glycosidases Inhibitors In the first part of this chapter, we described that deoxy-azasugars 150, 154 and pyrrolizidines 153 could be prepared from synthons 3 and 4, respectively. This method provides a structural diversity for the synthesis of many stereoisomers of azasugars, suitable for further studies of their glycosidase inhibitions. . In the second part, we explored a straightforward and convenient method for the synthesis of biologically interesting C-butenyl linked disaccharides using Grubbs’ ruthenium benzylidene as catalyst for olefin cross-metathesis reactions.
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"Studies on synthetic and naturally occurring glycosidase inhibitors from mushrooms." Chinese University of Hong Kong, 1994. http://library.cuhk.edu.hk/record=b5887198.
Full textAbstract:
Fung Pik Ha.Thesis (M.Phil.)--Chinese University of Hong Kong, 1994.
Includes bibliographical references (leaves 116-121).
Acknowledgments --- p.i
Table of Contents --- p.ii
List of Figures --- p.v
List of Tables --- p.x
Abstract --- p.xi
Chapter Chapter I --- Introduction --- p.1
Chapter Chapter II --- Literature Reviews
Chapter II.l --- Glycosidase --- p.3
Chapter II.2 --- Biosynthesis of N-linked Glycoprotein --- p.4
Chapter II.3 --- Mechanism of Enzyme Catalysed Reaction --- p.8
Chapter II.4 --- Types of Glycosidase Inhibitors --- p.12
Chapter II.5 --- Cyclophellitol and Aminocyclitols
Chapter II.5.1 --- General background on cyclophellitol --- p.17
Chapter II.5.2 --- Mode of inhibition of cyclophellitol --- p.20
Chapter II.5.3 --- General background on aminocyclitols --- p.24
Chapter Chapter III --- Characterization of Synthetic Glycosidase Inhibitors
Chapter III.1 --- Covalent-based Inactivator (Cyclophellitol and its Analogues)
Chapter III.1.1 --- Introduction --- p.28
Chapter III.1.2 --- Materials --- p.32
Chapter III.1.3 --- Methods
Chapter III.1.3.1 --- Inhibitory assay of commercially available glycosidases --- p.33
Chapter III.1.3.2 --- Partial purification of β-D-mannosidase from A. oryzae --- p.34
Chapter III.1.3.3 --- Protein assay in purification of β-D-mannosidase --- p.38
Chapter III.1.3.4 --- Inhibitory assay for partially purified β-D- mannosidase (A . oryzae) --- p.38
Chapter III.1.3.5 --- Influence of dialysis on glycosidase inhibition --- p.39
Chapter III.1.3.6 --- Inactivation experiment on glycosidases --- p.39
Chapter III.1.4 --- Results
Chapter III.1.4.1 --- Inhibitory activities of cyclophellitol and its analogues against glycosidases --- p.41
Chapter III.1.4.2 --- Effect of dialysis on glycosidase inhibition --- p.44
Chapter III.1.4.3 --- The kinetic studies of glycosidase inactivation --- p.47
Chapter III. 1.5 --- Discussion --- p.50
Chapter III.1.6 --- Further studies --- p.55
Chapter III.2 --- Reversible Competitive Inhibitors (Aminocyclitols)
Chapter III.2.1 --- Introduction --- p.56
Chapter III.2.2 --- Materials --- p.58
Chapter III.2.3 --- Methods
Chapter III.2.3.1 --- Assay of glucoside hydrolase inhibition activity --- p.60
Chapter III.2.3.2 --- Glucose oxidase method for determination of released D-glucose --- p.60
Chapter III.2.3.3 --- Inhibitory assay of aminocyclitols on other glycosidases --- p.61
Chapter III.2.3.4 --- Influence of dialysis on the glycosidase inhibition --- p.62
Chapter III.2.3.5 --- Lineweaver-Burk plot --- p.63
Chapter III.2.4 --- Results
Chapter III.2.4.1 --- Inhibitory activities of valiolamine and related aminocyclitols against six glycosidases --- p.64
Chapter III.2.4.2 --- Characterization the aminocyclitols as reversible competitive inhibitors --- p.69
Chapter III.2.5 --- Discussion --- p.80
Chapter Chapter IV --- Isolation of the Naturally Occurring Glycosidase Inhibitor from Mushrooms
Chapter IV.1 --- Introduction --- p.83
Chapter IV.2 --- Materials --- p.84
Chapter IV.3 --- Methods
Chapter IV.3.1 --- Preparation of Ganoderma lucidum --- p.86
Chapter IV.3.2 --- Preparation of V. volvacea --- p.86
Chapter IV.3.3 --- Inhibitory assay of aqueous extract of mushrooms on glycosidases --- p.87
Chapter IV.3.4 --- Anthrone method for determination of reducing sugars --- p.87
Chapter IV.3.5 --- Flash liquid chromatography for purification of putative inhibitors in G. lucidum --- p.88
Chapter IV.4 --- Results
Chapter IV.4.1 --- Prescreening of Inhibitory effects of Various Fungal Extracts --- p.90
Chapter IV.4.2 --- Inhibitory Effects of Partially Purified G. lucidum Extract on Glycosidase --- p.92
Chapter IV.4.3 --- Effect of Endogenous Substrates on Glycosidase Activities --- p.93
Chapter IV.4.4 --- Results of Liquid Column Chromatography --- p.93
Chapter IV.4.5 --- Structure Determination and Characterization of purified compounds --- p.95
Chapter IV.4.6 --- Inhibitory Activities of Compounds A and B against Brewers yeast a- glucosidase --- p.96
Chapter IV.5 --- Discussion --- p.98
Chapter Chapter V --- Conclusions --- p.113
References --- p.116
37
Chiang, Cheng-Fang, and 蔣呈凡. "Synthesis of 7-Hydroxymethyl-3,4,5-trihydroxyazepanes and Polyhydroxyperhydroazaazulenes for glycosidase inhibitors." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/76374430387067480094.
Full textAbstract:
碩士淡江大學
化學學系碩士班
95
Azasugars are considered as glycosidase inhibitors and possess potential in treatment of diabetes, cancers, and AIDS. Seven-membered azasugars were reported to be more conformationally flexible than the corresponding six- and five-membered counterparts, but little attention has been paid. We describe herein a new approach to the synthesis of diastereomeric 7-hydroxymethyl-3,4,5-trihydroxyazepanes in ten steps from D-(-)-quinic acid. We also compare the biological activities with C2-symmetrical tetrahydroxy -azepanes. In addition, 5,7-heterocyclic ring system of azasugars (called azaazulenes) are also considered to be potential glycosidase inhibitors. We have established an expeditious synthesis of newpolyhydroxyperhydroazaazulenes from trans-4-hydroxy-L-proline.
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張元軍. "Synthesis of N-alkyl Iminoalditol and pyrrolidine derivatives as Glycosidase Inhibitors." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/83759606820380930634.
Full textAbstract:
碩士國立彰化師範大學
化學系
97
The goals of our research are to synthesize glycosidase inhibitors. The first project is using D-ribose as starting material to synthesize the derivatives of ribopyranoside. We are successful to obtain the target compound methyl 2-C-(5-deoxy-2,3-di-O-isopropylidene-5 morpholinopropylamino-β-D-ribopyranosyl) acetate 7, methyl 2-C-(5-deoxy-2,3-di-O-isopropylidene-5-decylamino-β-Dribopyranosyl) acetate 9, 2-C-(5-deoxy-2,3-di-O-isopropylidene-5-morpholinopropyl amino-β-D-ribopyranosyl)ethanol 8, and 2-C-(5-deoxy-2,3-di-O-isopropylidene-5- decylamino -β-D-ribopyranosyl)ethanol 10 as shown in figure 1. The second project is using dimesylate as the starting materials to synthesize the derivatives of pyrrolidine. This study shows that amination reactions of dimesylate with various alkylamines can be substantially improved by microwave heating. This approach shortens reaction times from 1.5-72 h to 10-30 min and the yields are also improved. We are successful to obtain the target compound 1,2-bis-(2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino- L-ribitol-1-yl)ethane 21, bis(2-(2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino-L-ribitol-1-yl)ethyl)amine 22, and 1-(2-(2,3,5-Tri-O-benzyl-1,4-dideoxy-1,4-imino-L-ribitol-1- yl)ethyl)-4-((2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino-L-ribitol-1-yl)methyl)-1H-1,2,3-triazole 26 as shown in figure 1.
39
Liang, Ming-Tsung, and 梁名琮. "Synthesis of Polyhydorxylated 7-Alkylazepanes as Potent Glycosidase Inhibitors from D-(—)-Quinic acid." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/55451187134500140402.
Full textAbstract:
碩士淡江大學
化學學系碩士班
96
The biological activities of polyhydroxylated piperidines and their derivatives have been extensively studied during the past decades. These molecules are potentially therapeutic agents, especially, to serve as glycosidase inhibitors in treatment of cancers, diabetes and viral infections. The C- and N-alkylated piperidines are competitive glycosidase inhibitors to their corresponding molecules. Among them, deoxyfuconojirimycin (1,5-deoxy-1,5-imino-L-fucitol) was inhibitor against
40
Kuo, Wei-Shen, and 郭威伸. "Synthesis of a New Trihydroxy Piperidine Derivative for Glycosidase Inhibitor from D-(-)-Quinic Acid." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/86579139954835053864.
Full textAbstract:
碩士淡江大學
化學學系
92
Recently, the syntheses of glycosidase inhibitors have attracted a great deal of attention in academies and industries. These glycosidase inhibitors possess potential in the treatment of cancers, HIV, diabetes and metabolic disorders.The polyhydroxylated piperidines (called “azasugars” or “iminosugars”) have been known as glycosidase inhibitors. They display the same stereochemical information as common hexoses, but a nitrogen atom replaced the ring oxygen of the corresponding pyranose. Among these azasugars, the representative morecu1es, such as 1-deoxynojirimycin (DNJ) and 1-deoxymannojirimycin (DMJ), are strong inhibitors of glucosidase and mannosidase, respectively. Furthermore, 1,4,5-trideoxy-1,5-imino- D-lyxohexitol was synthesized from 3-deoxy- D-hexose and showed good inhibitory activity against theα-D-glucosidase, β-D- glucosidase andβ-D-galactosidase. Our ongoing project is aiming at the synthesis of various glycosidase inhibitors. Thus we reported a new 2,3-epi trihydroxy piperidine, (2S,4R,5S)-2-hydroxymethyl-piperidine-4,5- diol, which was synthesized in eleven steps starting from D-(-)-quinic acid.In addition, the family of quercitols possessed 16 stereoisomers. Among these isomers, (+)-proto-quercitol was isolated first in 1849 but its synthesis was not complete until 1968 by McCasland. We employed (1R,4R,5R)-triacetoxy-cyclohex-2-ene which was derived from the proper transformation of D-(-)-quinic acid to synthesize (+)-proto-quercitol. With the accomplishment from the above, we synthesize a series of protected chiral (1,4,5)-cyclohex-2-ene triols, which can be used in the syntheses of a variety of quercitols in the future
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Gunasundari, T. "Design, Synthesis and Applications of Novel Thiosugars & Amino Acid Derivatives." Thesis, 2012. http://hdl.handle.net/2005/3225.
Full textAbstract:
Glycosidases are carbohydrate processing essential enzymes necessary for the growth and development of all organisms such as intestinal digestion, post-translational processing of glycoproteins and the lysosomal catabolism of glycoconjugates. The function of these glycosidases is limited and studies are still in progress to understand their function at cellular level. In recent years, biological role of carbohydrates has resulted in various carbohydrate-based therapeutics2. These carbohydrates serve as a tool to study the function of glycosidases by inhibiting their active site. The concept of inhibition is yet another approach for the discovery of drugs.
Glycosidase inhibitors studied are often sugar analogs and a wide range of such inhibitors are reported in the literature.3, 4 Thiosugars, in particular, have gained new perspectives owing to their electronic, geometric, conformational and flexibility differences, as sulfide moiety being less electronegative and more polarizable than the oxygen counter-part.5 These differences make the thiosugars distinct from their oxygen analogs and hence can mimic the active site of the enzyme. Many molecules are reported to be promising glycosidase inhibitors but are not easily accessible due to difficulties in their synthesis. Hence, the chemical synthesis of thio-analogs of carbohydrates, by synthetic routes, remains a major challenge. To address the complexity of synthesis and to make available new strategies, we envisioned the use of benzyltriethylammonium tetrathiomolybdate [BnEt3N]2MoS4, a versatile and efficient sulfur transfer reagent.
Objectives of the study:
a. Design novel thiosugars as glycosidase inhibitors.
b. Devise strategy for the synthesis of novel thiosugars through a simple, practical approach.
c. Evaluate the synthesized molecules as glycosidase and HIV-1 protease inhibitors, in silico.
d. Study miscellaneous applications of the novel thiosugar-derived thialactones.
The thesis is divided into five sections:
Section A entitled “Synthesis of deoxythiosugars and thiosugar-based lactones” is divided into two parts, Part A and Part B.
Part A – “An introduction and background on thiosugars and sulfur transfer reagents” has been provided. A brief discussion of sulfur transfer reagents in carbohydrate synthesis and earlier work related to the use of benzyltriethylammonium tetrathiomolybdate, [BnEt3N]2MoS4, as an efficient sulfur transfer reagent have been provided.
Part B –“Design of inhibitors of glycosidases and HIV-1 protease” deals with the design of inhibitors of glycosidase and HIV-1 protease. The designed thiosugar molecules exhibit the characteristics of sugars and will act as planar molecules to mimic the active site conformation of a good inhibitor. Synthetic methodologies devised and adopted for the synthesis of constrained sugar-derived thialactones include: (a) Double displacement, (b) Displacement-cum-intramolecular thia-Michael addition, (c) Epoxide ring-opening-cum-intramolecular thia-Michael addition, and (d) Displacement-cum-epoxide ring opening in an intramolecular fashion. In all the above mentioned strategies, sulfur transfer step is the crucial step which was achieved by the use of benzyltriethylammonium tetrathiomolybdate [BnEt3N]2MoS46 as the key reagent.
(a) Various constrained thialactones synthesized by double displacement strategy using tetrathiomolybdate as the sulfur transfer reagent are shown in Scheme – 1.
(b) A number of constrained thialactones were synthesized following nucleophilic displacement-cum-intramolecular thia-Michael addition strategy as shown in Scheme – 2.
(c) Synthesis of bicyclic thiolactones was achieved using the strategy of epoxide ring-opening-cum-intramolecular thia-Michael addition. (Scheme – 3)
(d) A few bicyclic thialactones were synthesized through displacement-epoxide ring opening-cyclization as shown in Scheme – 4.
The methodology was also utilized for the synthesis of thiosugar derivatives and azido-thialactones. (Fig. 1)
Figure 1
Synthesis of deoxythiosugars: The bicyclic thialactones (designed as inhibitors) on reduction with borohydride exchange resin (BER) easily furnished the deoxythiosugars (Fig. 2). It is worth mentioning that the synthesis of these thiosugars as reported in the literature involved lengthy procedures whereas the present methodology turns out to be short and concise.
Figure 2
Section B entitled “Synthesis of amines, β-amino acids and novel thiosugar-based dehydroamino acids” comprises a brief introduction on the importance of amines, β-amino acids and dehyroamino acids. In this section the effective utilization of benzyltriethylammonium tetrathiomolybdate as a key reagent for reductive transformations and its application in the synthesis of amines, β-amino acids and dehyroamino acids have been presented.
A one pot reduction of azides to amines followed by intermolecular aza-Michael addition employing tetrathiomolybdate was achieved to furnish a number of different β-amino esters as shown in Scheme -4:
Scheme 4
The study was further extended to the reduction of a few anomeric azides to afford the corresponding anomeric amines and derivatives. (Fig. 3)
Figure 3
A one-pot thia-Michael addition-vinyl azide reduction in a tandem fashion employing benzyltriethylammonium tetrathiomolybdate was studied and was shown to be effective for the synthesis of thiosugar derived dehydroamino acid derivatives. (Scheme – 5)
Scheme 5
Section C entitled “Molecular docking studies of deoxythiosugar probes” gives an overview of different glycosidases, HIV-1 protease and their inhibitors. This section also deals with a brief introduction on active site conformations of potent inhibitors. In this connection we have studied the crystal conformations of the synthesized molecules whose conformations were the same as that of the existing inhibitors in the active site. (Fig. 4) With this background in silico study of the synthesized deoxythiosugar probes was conducted on human glycosidases: α-mannosidase, α-galactosidase, β-glucosidase and HIV-1 protease, respectively.
Figure 4
Molecular docking was carried out using Autodock suite, molecular modeling simulation. Separate docking procedures were employed for the four different receptors. The PDBs representing the four enzyme targets were 2V3D, 3H53, 1X9D and 3I8W for β–glucosidase, α–galactosidase, α–mannosidase and HIV–1 protease respectively. The control compounds used for α–mannosidase were mannostatin and kifunensine. NMB, THK, and BED were the positive controls for HIV–1 protease. Similarly, NBV and cyclophellitol were the controls used for β–glucosidase and NOJ, N–methyl calystegine B2 for α–galactosidase. (Fig. 5) Ligands TGSB68 and TGSB482 had the energy value of –6.49 kcal/mol comparable to that of the average reference value of the positive control, and thus, the potent candidate as identified by molecular docking to HIV-1 protease. (Fig. 6a) The control compounds used for α–mannosidase were mannostatin and kifunensine, which bind with mean binding energy of -9.11 and -5.56. In the case of α–mannosidase, the same compounds TGSB68 and TGSB482 were selected due to comparable energy and a good cluster size with that of positive control. (Fig. 6b) For β– glucosidase, ligands TGSC108 and TGSC236, which had comparable values to that of positive control was identified as the
Figure 5
Figure 6
potent candidate. (Fig. 6c) In the case of α–galactosidase, again the ligands TGSB68 and TGSB482 were selected based on binding energies. (Fig. 6d)
In conclusion, the concept analogy (deoxy nature, planarity, thiosugar framework, lactone moiety) for the design of inhibitors indeed worked positively. The results are really encouraging. An in vivo study of the synthesized novel thiosugar probes will certainly provide a potent inhibitor.
Section D entitled “Research methodology” provides experimental procedures adopted with details of synthesis.
Section E entitled “Bibliography” provides the references cited in this work.