University of North Florida
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Stuart Chalk, Ph.D.
Department of Chemistry
University of North Florida
Phone: 1-904-620-1938
Fax: 1-904-620-3535
Email: schalk@unf.edu
Website: @unf

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Combinatorial chemistry

Classification: Reaction -> Combinatorial chemistry

Citations 7

"FTICR-Mass Spectrometry For High-resolution Analysis In Combinatorial Chemistry"
Biotechnol. Bioeng. 2000 Volume 71, Issue 2 Pages 149-161
Dietmar G. Schmid, Philipp Grosche, Holger Bandel, Günther Jung

Abstract: The diversity of compound collections required for finding lead structures in pharmaceutical research can be provided by means of combinatorial organic chemistry. The resultant enormous number of single compounds but also of compound mixtures represents a challenge for the analyst. With the introduction of Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS or FT-MS), a new and, as yet, not widespread mass spectrometric technique (a means of analysis of such compound libraries with a very high mass resolution) high mass accuracy and high sensitivity has become available. Moreover, in combination with electrospray ionization (ESI), not only high-th rough put measurements via flow injection analysis (FIA) but also coupling with separation techniques such as high-performance liquid chromatography (HPLC) or capillary electrophoresis (CE) is possible. Structural verification by way of decomposing ions (MSn; n greater than or equal to 2) using a variety of different dissociation techniques can be performed by FTICR-MS. This is the first review specifically covering applications of FTICR-MS in the field of combinatorial chemistry.

"FTIR Spectroscopy As Detection Principle In Aqueous Flow Analysis"
Anal. Commun. 1999 Volume 36, Issue 4 Pages 123-126
R. Schindler and B. Lendl

Abstract: Whereas FTIR spectroscopic detection is routinely used in gas chromatography (B. Erikson, Anal. Chem., 1998, 70, 801A), its use for liquid chromatography (LC) and flow injection analysis (FIA) is a rather exotic exception. The most prominent reason is the strong IR absorption of most of the common solvents, especially water. Hence FTIR spectroscopy is normally not even considered a valuable detection method. This practice neglects that FTIR spectroscopy offers some unique features which now, using modern instrumentation, can be exploited in an advantageous manner. It is the aim of this Highlight article to demonstrate the wide range of possible applications in LC and FIA. To regard FTIR spectroscopy as too exotic for routine use may be a luxury paid for with the neglect of a simple analytical approach. The term flow analysis (FA) will be used to provide a common cover for both LC and FIA because both rely on the injection of a sample into a flowing stream, passage through a modulator and recording of transient peaks. Although the processes taking place in the modulator are different, being chemical reactions in FIA and separations in LC, the same interfaces can be used for a FTIR spectrometer as a detector. The interfaces used can be divided into two categories, flow through cells where the liquid is probed directly, and solvent removal interfaces where the analyte is separated from the carrier liquid prior to detection. It is necessary to emphasize the complementary nature of these techniques (D. E. Pivonka and K. M. Kirkland, Appl. Spectrosc., 1997, 51, 866) and this Highlight will stress their particular strengths and weaknesses. Special focus is laid on aqueous phase systems because of their high importance in biological systems. As water is certainly the most challenging solvent for IR detection, equal or even better performance of the presented approaches can be expected for other solvents. Additionally three developments will be discussed in detail with respect to their prospects for FA-FTIR instruments: the increasing availability of sophisticated chemometric methods, the miniaturization of analytical instruments and application to combinatorial chemistry.

"The Automatic Visualisation Of Carry-over In High-throughput Flow Injection Analysis Mass Spectrometry"
Anal. Chim. Acta 1999 Volume 390, Issue 1-3 Pages 175-183
Ramsay Richmond and Ekkehard Görlach

Abstract: A high-throughput flow injection analysis mass spectrometry system (FIA-MS) was developed for the purity estimation of multiple parallel combinatorial chemistry synthetic samples, and has measured over 70 000 samples in two years. An in-house Visual Basic application called RackViewer allows a fast, direct, easy and economic inspection of the estimates at geographically dispersed laboratory workbenches via the corporate network. Due to the large numbers of samples involved, surreptitious inter-sample carry-over represents one threat to the accuracy of these purity estimates. It can become serious when reducing the measurement duty cycle in order to develop faster throughput rates. Over 400 samples drawn equally from five different combinatorial synthetic families were measured to explore this threat. By analogy with the color rendering of the purity estimates, inter-sample carry-over was automatically calculated for each measurement, color rendered and then depicted within RackViewer. Our FIA-MS in daily use has a median basal carry-over of 0.88%.

"Sorting Measurement Queues To Speed Up The Flow Injection Analysis Mass Spectrometry Of Combinatorial Chemistry Syntheses"
Anal. Chim. Acta 1999 Volume 394, Issue 1 Pages 33-42
Ramsay Richmond and Ekkehard Görlach

Abstract: A high-throughput flow injection analysis mass spectrometry system was developed for the purity estimation of multiple parallel combinatorial chemistry synthetic samples. Surreptitious inter-sample carry-over represents a threat to the accuracy of the purity estimates. The visualisation of carry-over in 96-well racks via a surveillance program was improved by introducing the automatic sorting of the intra-rack sample measurement queues. This was necessary as the logical arraying of building blocks by synthetic dispensing robots imparts an underlying row and/or column order to the 96-well racks, which complicates the estimation of carry-over. In a primary sorting step, the molecular weight difference between the expected synthetic products in consecutively measured wells was maximised; in a secondary sorting step, the consecutive measurement of wells with similar building blocks was minimised. Over four hundred samples drawn equally from five diverse combinatorial synthetic families were measured to explore the use of this two-stage sorting to ease the measurement of carry-over, and so to facilitate the optimization of the flow injection analysis measurement duty cycle. Subsequently the duty cycle in daily use, of 168 s was reduced to 70 s, while maintaining the median inter-sample carry-over at levels below 1%.

"The Analytical Characterisation Of Sub-minute Measurement Duty Cycles In Flow Injection Analysis Mass Spectrometry, By Their Carry-over"
Anal. Chim. Acta 2000 Volume 403, Issue 1-2 Pages 287-294
Ramsay Richmond

Abstract: A high-throughput flow injection analysis mass spectrometry system was developed in-house for the purity estimation of multiple parallel combinatorial chemistry syntheses. A Visual Basic application called RackViewer allows a fast and easy on-screen inspection of these estimates at dispersed laboratory workbenches via the corporate computer network. Due to the increasing numbers of samples to be measured, there is an constant incentive to reduce the measurement duty cycle in order to develop faster throughput rates. Consequently, one threat to the accuracy of these purity estimates is surreptitious inter-sample carry-over. By analogy with the computer screen color rendering of the purity estimates, carry-over was automatically calculated, then color depicted within RackViewer. In an earlier report, this carry-over visualisation tool facilitated a stepwise reduction in the measurement duty cycle to 70 s, while maintaining median inter-sample carry-over at levels well below 1%. However, a limiting factor in further optimization was the physical speed of the autosamplers sampling head. A recent increase in this speed by the autosamplers manufacturer allowed a second attempt at achieving well characterized sub-minute measurement duty cycles. Six injection variations involving different syringe and loop wash combinations were examined for their characteristic inter-sample carry-over, using over four hundred samples drawn equally from five diverse combinatorial chemistries. One emerged as the best, with a median inter-sample carry-over of 0.01% and a measurement duty cycle of 44 s.
Mass spectrometry

"High-throughput Flow Injection Analysis Mass Spectrometry With Networked Delivery Of Color Rendered Results: The Characterisation Of Liquid Chromatography Fractions"
J. Chromatogr. A 1999 Volume 835, Issue 1-2 Pages 29-39
Ramsay Richmond, Ekkehard Görlach and Jan-Marcus Seifert

Abstract: An automated high-throughput flow injection analysis electrospray-mass spectrometry system originally developed in-house for purity estimation of multiple parallel synthesis combinatorial chemistry samples, was adapted to analyze liquid chromatography fractions. A networked Visual Basic application called RACKVIEWER provides a fast and easy inspection of color rendered liquid chromatography fraction data, by the synthetic chemists, whether at the main corporate site or the various geographically dispersed Novartis Pharma research institutes. Various depictions of individual well ion currents including colorised three-dimensional maps of the racks entire ion current, provide data highlighting strategies. Other advantages include allowing the seamless integration of 96-well racks containing the Liquid chromatography fractions into existing quick turnaround high-throughput mass spectrometry queues, and allowing the synthetic chemists a wider a priori choice of MS compatible chromatographic conditions.

"AutoScan: An Automated Workstation For Rapid Determination Of Mass And Tandem Mass Spectrometry Conditions For Quantitative Bioanalytical Mass Spectrometry"
Rapid Commun. Mass Spectrom. 2000 Volume 14, Issue 21 Pages 2074-2079
Kevin M. Whalen, Katrina J. Rogers, Mark J. Cole, John S. Janiszewski

Abstract: An automated flow injection analysis (FIA) mass spectrometry system (AutoScan) was developed to allow rapid unattended determination of optimal conditions during mass (ms) and tandem mass spectrometry (ms/ms) on new chemical entities (NCEs) arranged in 96-well plates, The 96-well plate Is placed on the deck of a modified Gilson Multiprobe autosampler for injection into a PE Sciex API 2000 triple quadrupole mass spectrometer, A customized software interface is used to create the necessary scan experiments by associating each 96-well plate of NCEs to be scanned with an index file containing data on the identity of each analyte and its expected molecular weight. Analytes are injected four at a time into a custom injection manifold and conventional mass spectra are acquired in both polarities (±) using an alternating positive/negative Q1 scan function. The software determines the optimal polarity and definitive precursor ion for all analytes and uses the results to build the Injection sequence for product ion scanning. The samples are automatically re-injected under MS/MS conditions, and product ion scans that loop among different collision energies are collected for each analyte. The resulting data are processed automatically and the optimal MS/MS transitions for each analyte are selected. A color-coded graphical interface facilitates data review, Any unusual ion transitions or transposition errors made during plate preparation are noted and corrected. Complete MS and MS/MS conditions are obtained for 96 compounds in about one hour and the resulting data are available for download as sample control injection sequence files.