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Biomedical subjects

Paul Watts

Publications and source records attributed to Paul Watts.

17 recordsLinked to original sources
PubMed2006

Scaling out of electrolyte free electrosynthesis in a micro-gap flow cell.

The electro-reductive coupling of activated olefins and benzyl bromide derivatives has been selected to compare the performance of single and multiple channel (scaled-out) micro-gap electrochemical flow reactors. Two working electrode configurations were evaluated; in the first a single set of electrodes was used in conjunction with a multiple flow manifold to give two and four separate flow channels; in the second independent electrodes were used within the same flow manifold. Problems with shunt currents and Joule heating in the first configuration meant that only the second configuration was reliable, giving results comparable to those obtained for the single flow cell. Excellent yields of the coupling products such as 2-benzyl-succinic acid dimethyl ester and derivatives were obtained. This demonstrates micro reactor scale-out for unsupported electrosyntheses.

Journal Article↗
PubMed2006

Efficient protein digestion with peptide separation in a micro-device interfaced to electrospray mass spectrometry.

A highly efficient protein digestion device has been fabricated using commercially available immobilized trypsin on agarose beads, packed into a silica capillary and connected either directly to an electrospray mass spectrometer via a 'microtight T' connector, from which aqueous acetic acid (0.2%) was pumped, or via a monolithic column connected to the mass spectrometer ion source. Six proteins with molecular mass ranging from 2848 to 77703 Da were digested completely using this system. In the second set of experiments a short monolithic separation column was placed after the immobilized trypsin capillary and partial separation of the generated peptides was obtained. The detection limits were increased from the micromol to pmol range by utilization of this separation column. Gradient elution, using a binary HPLC pump and a flow splitter, was used to optimize the peptide separation. This provided significantly enhanced resolution of the tryptic peptides but increased the analysis time to 30 minutes.

Chromatography, High Pressure Liquid↗
PubMed2005

Assembly intermediates in polyketide biosynthesis: enantioselective syntheses of beta-hydroxycarbonyl compounds.

A versatile approach for the enantioselective synthesis of functionalised beta-hydroxy N-acetylcysteamine thiol esters has been developed which allows the facile incorporation of isotopic labels. It has been shown that a remarkable reversal of selectivity occurs in the titanium mediated aldol reaction of acyloxazolidinone using either (S)- or (R)-tert-butyldimethylsilyloxybutanal. The aldol products are valuable intermediates in the synthesis of 4-hydroxy-6-substituted delta-lactones.

Ketones↗
PubMed2005

The application of micro reactors for organic synthesis.

This tutorial review describes how micro reactors are being applied to synthetic chemistry covering a wide range of applications, from the preparation of nanograms of material for drug discovery and screening to the multi-tonne production of fine chemicals. This article explores how miniaturisation may revolutionise chemical synthesis and demonstrates that products are generated in higher yield and purity compared to the equivalent bulk reactions, in much shorter periods of time.

Combinatorial Chemistry Techniques↗
PubMed2004

Syntheses of 11C- and 18F-labeled carboxylic esters within a hydrodynamically-driven micro-reactor.

Carboxylic esters were successfully labeled with one of two short-lived positron-emitters, carbon-11 or fluorine-18, within a hydrodynamically-driven micro-reactor. The non-radioactive methyl ester was obtained at room temperature; its yield increased with higher substrate concentration and with reduced infusion rate. Radioactive methyl ester was obtained from the reaction of (10 mM) with in 56% decay-corrected radiochemical yield (RCY) at an infusion rate of 10 microL min(-1), and when the infusion rate was reduced to 1 microL min(-1), the RCY increased to 88%. The synthesis of the non-radioactive fluoroethyl ester from and required heating of the micro-reactor on a heating block at 80 degrees C (14-17% RCY), whilst the corresponding radioactive from and was obtained in 10% RCY. The radioactive 'peripheral' benzodiazepine receptor ligand was obtained from the reaction of acid with labeling agent in 45% RCY at an infusion rate of 10 microL min(-1). When the infusion rate was reduced to 1 microL min(-1), the RCY increased to 65%. The results exemplify a new methodology for producing radiotracers for imaging with positron emission tomography that has many potential advantages, including a requirement for small quantities of substrates, enhanced reaction, rapid reaction optimisation and easy product purification.

Carbon Dioxide↗
PubMed2004

Organic synthesis in micro reactors.

This article reviews the current and future applications of micro reactors in the field of chemistry, biochemistry and drug discovery. The fabrication and physical characterisation of micro reactors, together with details of their use and operation is described. Liquid and gas phase reactions have been used to illustrate the advantages of performing chemical reactions in micro reactors. A brief evaluation of the possible advantages that micro fabrication could offer in developing biological applications, based on miniaturized devices is also presented.

Biosensing Techniques↗
PubMed2004

Continuous flow microreactors for drug discovery.

This article reviews the use of microreactors in the field of organic and combinatorial synthesis with regard to drug discovery applications. Research conducted into microreactors that enable in situ purification is described, and it is proposed that compounds could potentially be screened within an integrated bioassay system. A description of how it would be possible to use this technology to prepare larger quantities of pharmaceutical intermediates is also given.

Biological Assay↗
PubMed2003

Continuous flow reactors for drug discovery.

To develop a new generation of drugs, pharmaceutical companies need to be able to synthesize and screen novel chemicals with enhanced speed. New technology that would enable a cost-neutral increase in the number of potential drug candidates would provide a distinct competitive advantage. The miniaturisation of chemical reactors offers many fundamental and practical advantages of relevance to the pharmaceutical industry, which is constantly searching for controllable, information-rich, high-throughput and environmentally friendly methods of producing compounds with a high degree of chemical selectivity. This article reviews the current and future applications of micro reactors that could enhance the drug discovery process.

Chemistry, Pharmaceutical↗
PubMed2003

X-ray crystallographic and kinetic studies of human sorbitol dehydrogenase.

Sorbitol dehydrogenase (hSDH) and aldose reductase form the polyol pathway that interconverts glucose and fructose. Redox changes from overproduction of the coenzyme NADH by SDH may play a role in diabetes-induced dysfunction in sensitive tissues, making SDH a therapeutic target for diabetic complications. We have purified and determined the crystal structures of human SDH alone, SDH with NAD(+), and SDH with NADH and an inhibitor that is competitive with fructose. hSDH is a tetramer of identical, catalytically active subunits. In the apo and NAD(+) complex, the catalytic zinc is coordinated by His69, Cys44, Glu70, and a water molecule. The inhibitor coordinates the zinc through an oxygen and a nitrogen atom with the concomitant dissociation of Glu70. The inhibitor forms hydrophobic interactions to NADH and likely sterically occludes substrate binding. The structure of the inhibitor complex provides a framework for developing more potent inhibitors of hSDH.

Binding Sites↗
PubMed2003

Microfluidic combinatorial chemistry.

Microreactors are finding increasing application in the field of combinatorial chemistry. In the past few years, microreactor chemistry has shown great promise as a novel method on which to build new chemical technology and processes. It has been conclusively demonstrated that reactions performed within microreactors invariably generate relatively pure products in high yield. One of the immediate and obvious applications is therefore in combinatorial chemistry and drug discovery.

Combinatorial Chemistry Techniques↗
PubMed2002

Investigation of racemisation in peptide synthesis within a micro reactor.

We demonstrate that peptides derived from alpha-amino acids may be prepared in a micro reactor. The peptides were prepared in 20 min with quantitative conversion, compared to batch reactions which require prolonged reaction times. We illustrate that by using dilute reagent concentrations and short reaction times, less racemisation is observed in micro reactions than in bulk reactions.

Indicators and Reagents↗