White A.F.B.,Dextra Laboratories Ltd. |
Demchenko A.V.,University of Missouri-St. Louis
Advances in Carbohydrate Chemistry and Biochemistry | Year: 2014
Sepsis, defined as a clinical syndrome brought about by an amplified and dysregulated inflammatory response to infections, is one of the leading causes of death worldwide. Despite persistent attempts to develop treatment strategies to manage sepsis in the clinical setting, the basic elements of treatment have not changed since the 1960s. As such, the development of effective therapies for reducing inflammatory reactions and end-organ dysfunction in critically ill patients with sepsis remains a global priority. Advances in understanding of the immune response to sepsis provide the opportunity to develop more effective pharmaceuticals. This article details current information on the modulation of the lipopolysaccharide (LPS) receptor complex with synthetic Lipid A mimetics. As the initial and most critical event in sepsis pathophysiology, the LPS receptor provides an attractive target for antisepsis agents. One of the well-studied approaches to sepsis therapy involves the use of derivatives of Lipid A, the membrane-anchor portion of an LPS, which is largely responsible for its endotoxic activity. This article describes the structural and conformational requirements influencing the ability of Lipid A analogues to compete with LPS for binding to the LPS receptor complex and to inhibit the induction of the signal transduction pathway by impairing LPS-initiated receptor dimerization. © 2014 Elsevier Inc.
Brown K.,University of Southampton |
Brown K.,Dextra Laboratories Ltd |
Dixey M.,University of Southampton |
Weymouth-Wilson A.,Dextra Laboratories Ltd |
Linclau B.,University of Southampton
Carbohydrate Research | Year: 2014
Gemcitabine is a fluorinated nucleoside currently administered against a number of cancers. It consists of a cytosine base and a 2-deoxy-2,2- difluororibose sugar. The synthetic challenges associated with the introduction of the fluorine atoms, as well as with nucleobase introduction of 2,2-difluorinated sugars, combined with the requirement to have an efficient process suitable for large scale synthesis, have spurred significant activity towards the synthesis of gemcitabine exploring a wide variety of synthetic approaches. In addition, many methods have been developed for selective crystallisation of diastereomeric (including anomeric) mixtures. In that regard, the 2-deoxy-2,2-difluororibose sugar is one of the most investigated fluorinated carbohydrates in terms of its synthesis. The versatility of synthetic methods employed is illustrative of the current state of the art of fluorination methodology for the synthesis of CF2-containing carbohydrates, and involves the use of fluorinated building blocks, as well as nucleophilic and electrophilic fluorination of sugar precursors. © 2014 Published by Elsevier Ltd.
Linclau B.,University of Southampton |
Wang Z.,University of Southampton |
Compain G.,University of Southampton |
Paumelle V.,University of Southampton |
And 3 more authors.
Angewandte Chemie - International Edition | Year: 2016
Property tuning by fluorination is very effective for a number of purposes, and currently increasingly investigated for aliphatic compounds. An important application is lipophilicity (log P) modulation. However, the determination of log P is cumbersome for non-UV-active compounds. A new variation of the shake-flask log P determination method is presented, enabling the measurement of log P for fluorinated compounds with or without UV activity regardless of whether they are hydrophilic or lipophilic. No calibration curves or measurements of compound masses/aliquot volumes are required. With this method, the influence of fluorination on the lipophilicity of fluorinated aliphatic alcohols was determined, and the log P values of fluorinated carbohydrates were measured. Interesting trends and changes, for example, for the dependence on relative stereochemistry, are reported. © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
Looking glass inhibitors: scalable syntheses of DNJ, DMDP, and (3R)-3-hydroxy-l-bulgecinine from d-glucuronolactone and of l-DNJ, l-DMDP, and (3S)-3-hydroxy-d-bulgecinine from l-glucuronolactone. DMDP inhibits β-glucosidases and β-galactosidases whereas l-DMDP is a potent and specific inhibitor of α-glucosidases
Best D.,University of Oxford |
Wang C.,University of Oxford |
Weymouth-Wilson A.C.,Dextra Laboratories Ltd |
Clarkson R.A.,Dextra Laboratories Ltd |
And 5 more authors.
Tetrahedron Asymmetry | Year: 2010
A convenient large-scale synthesis of 1-deoxynojirimyin (DNJ) from d-glucuronolactone involves introduction of azide at C-5 with retention of configuration to give 5-azido-5-deoxy-1,2-O-isopropylidene-α-d-glucofuranose as a key intermediate in an overall yield of up to 72%; the same intermediate can be transformed into DMDP [(2R,3R,4R,5R)-2,5-bis(hydroxymethyl)pyrrolidine-3,4-diol] and (3R)-3-hydroxy-l-bulgecinine [(2S,3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-l-proline]. l-Glucuronolactone, a readily available l-sugar chiron, may similarly be used to access the enantiomers l-DNJ, l-DMDP, and (3S)-3-hydroxy-d-bulgecinine. A comparison of glycosidase inhibition by DMDP (an inhibitor of β-glucosidases and β-galactosidases) and l-DMDP (a potent and specific α-glucosidase inhibitor) with the corresponding enantiomeric hydroxybulgecinines is reported; DMDP and (3R)-3-hydroxy-l-bulgecinine show weak inhibition of glycogen phosphorylase. © 2010 Elsevier Ltd. All rights reserved.
Peterson K.,Lund University |
Weymouth-Wilson A.,Dextra Laboratories Ltd. |
Nilsson U.J.,Lund University
Journal of Carbohydrate Chemistry | Year: 2015
A method of using benzenesulfonates and imidazylates as leaving groups at the secondary C3 galactopyranose carbon, instead of the commonly used less stable triflate leaving group, to facilitate scale-up and improve reproducibility is disclosed. The benzenesulfonates and imidazylates were proven to be significantly more stable than the corresponding triflates and the method was used to devise an improved route toward 3-Azido-3-deoxy-β-d-galactopyranosides. Copyright © 2015 Taylor & Francis Group, LLC.
Lenagh-Snow G.M.J.,University of Oxford |
Araujo N.,University of Oxford |
Jenkinson S.F.,University of Oxford |
Rutherford C.,University of Oxford |
And 5 more authors.
Organic Letters | Year: 2011
Efficient ring closure of stable crystalline 3,5-di-O-triflates of pentofuranosides with amines to form azetidines allowed preliminary evaluation of four-ring iminosugars as glycosidase inhibitors; significant and specific inhibition of nonmammalian α-glucosidases is shown by l-xylo- and l-arabino-iminosugar azetidines. © 2011 American Chemical Society.
Cowper B.,University College London |
Sze T.M.,University College London |
Premdjee B.,University College London |
Bongat White A.F.,Dextra Laboratories Ltd |
And 2 more authors.
Chemical Communications | Year: 2015
3/4-Mercaptobenzyl sulfonates were investigated as aryl thiol catalysts for native chemical ligation (NCL). Whilst catalysing NCL processes at a similar rate to 4-mercaptophenyl acetic acid (MPAA), the increased polarity and solubility of 3-mercaptobenzyl sulfonate in particular may favour its selection as NCL catalyst in many instances. This journal is © The Royal Society of Chemistry 2015.
Agency: GTR | Branch: Innovate UK | Program: | Phase: Innovation Voucher | Award Amount: 5.00K | Year: 2014
NZP-Dextra manufactures bile acids used principally in the manufacture of the liver drug ursodeoxycholic acid and carbohydrates for drug actives and medical research. The company will use its innovation voucher to further develop and improve its manufacturing processes.
PubMed | University of Nantes, University of Southampton and Dextra Laboratories Ltd
Type: | Journal: Chemistry (Weinheim an der Bergstrasse, Germany) | Year: 2016
Rational modulations of molecular interactions are of significant importance in compound properties optimization. We have previously shown that fluorination of conformationally rigid cyclohexanols leads to attenuation of their hydrogen-bond (H-bond) donating capacity (designated by pK
PubMed | University of Southampton and Dextra Laboratories Ltd
Type: Journal Article | Journal: Angewandte Chemie (International ed. in English) | Year: 2016
Property tuning by fluorination is very effective for a number of purposes, and currently increasingly investigated for aliphatic compounds. An important application is lipophilicity (logP) modulation. However, the determination of logP is cumbersome for non-UV-active compounds. A new variation of the shake-flask logP determination method is presented, enabling the measurement of logP for fluorinated compounds with or without UV activity regardless of whether they are hydrophilic or lipophilic. No calibration curves or measurements of compound masses/aliquot volumes are required. With this method, the influence of fluorination on the lipophilicity of fluorinated aliphatic alcohols was determined, and the logP values of fluorinated carbohydrates were measured. Interesting trends and changes, for example, for the dependence on relative stereochemistry, are reported.