Rapid deconvolution of combinatorial libraries using HPLC fractionation

Griffey, Richard H.; An, Hongyu; Cummins, Lendell L.; Gaus, Hans; Haly, Becky D.; Herrmann, R. A.; Cook, P. Dan

doi:10.1016/s0040-4020(98)00135-5

Cited by 21 publications

(15 citation statements)

References 17 publications

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“…A number of deconvolution approaches have been presented, the most commonly used being iterative, , positional scanning, and the sequencing of resin-bound peptides or tags from one-bead−one-compound libraries. ,, While straightforward, the iterative approach is an inherently time-consuming deconvolution method due to the repetitive rounds of synthesis and testing, requiring the same number of syntheses as the original number of nondefined diversity positions in the library. Other deconvolution methods include orthogonal pooling, subtractive pooling, − bogus coin pooling, , indexed pooling, libraries of libraries, affinity separation, − and mass spectrometry based strategies. The theoretical and comparative evaluations of these methods have been reported. ,, …”

Section: Deconvolution Strategies Of Mixture-based Librariesmentioning

confidence: 99%

“…Using this technique, ligand−receptor complexes in solution following ultrafiltration can be determined by electrospray mass spectrometry. Similar deconvolution approaches involve the separation of ligand−receptor complex from unbound compounds by size exclusion chromatography followed by identification of bound ligand by electrospray mass spectrometry 75,76 or successive fractionations by HPLC followed by mass spectrometry analysis of the library and active fractions . These different analytical-based deconvolution approaches to date have been used only for relatively small libraries (i.e., containing up to 4 000 individual compounds).…”

Section: Deconvolution Strategies Of Mixture-based Librariesmentioning

confidence: 99%

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Mixture-Based Synthetic Combinatorial Libraries

et al. 1999

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Section: Deconvolution Strategies Of Mixture-based Librariesmentioning

confidence: 99%

Section: Deconvolution Strategies Of Mixture-based Librariesmentioning

confidence: 99%

Mixture-Based Synthetic Combinatorial Libraries

et al. 1999

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“…Auch wenn zwei stereogene Elemente miteinander verbundenen sind oder bei einer Verknüpfung entstehen, sollte es vorteilhaft sein, zunächst die Racemate von zwei oder drei Diastereomeren am biologischen Target zu testen 22. Mit der schneller werdenden Entwicklung verbesserter Analysenmethoden und Trenntechniken zur Dekonvolution komplexer Mischungen23 können die stereochemischen Anforderungen an Aufbaureaktionen künftig sogar noch weiter gesenkt werden.…”

Section: Das Problem Aus Der Sicht Der Verfahrensentwicklungunclassified

Click-Chemie: diverse chemische Funktionalität mit einer Handvoll guter Reaktionen

Kolb¹,

2001

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Betrachtet man die in der Natur am häufigsten vorkommenden Verbindungen, so fällt auf, dass die Bildung von Kohlenstoff‐Heteroatom‐Bindungen gegenüber der von Kohlenstoff‐Kohlenstoff‐Bindungen deutlich bevorzugt ist. Da zum einen Kohlendioxid die Basisverbindung der Natur ist und andererseits das Medium natürlicher Reaktionen zumeist Wasser ist, überrascht dies sicherlich nicht. Nucleinsäuren, Proteine und Polysaccharide sind polymere Kondensationsprodukte kleiner Untereinheiten, die durch Kohlenstoff‐Heteroatom‐Bindungen verknüpft sind. Sogar die etwa 35 Baueinheiten, aus denen diese essentiellen Verbindungen bestehen, enthalten nicht mehr als sechs aufeinander folgende C‐C‐Bindungen, sieht man einmal von den drei aromatischen Aminosäuren ab. Mit der Natur als Vorbild richteten wir unser Interesse auf die Entwicklung leistungsfähiger, gut funktionierender und selektiver Reaktionen für die effiziente Synthese neuartiger nützlicher Verbindungen sowie kombinatorischer Bibliotheken mittels Heteroatomverknüpfungen (C‐X‐C). Diese Synthesestrategie nennen wir „Click‐Chemie“. Click‐Chemie ist durch eine Auswahl einiger weniger nahezu idealer Reaktionen charakterisiert, mit all ihren Grenzen und Möglichkeiten. In diesem Beitrag werden zum einen die strengen Kriterien, die Reaktionen erfüllen müssen, um die Bezeichnung „Click‐Chemie“ zu verdienen, definiert, zum anderen werden Beispiele für molekulare Strukturen gegeben, die mit dieser spartanischen, aber dennoch leistungsfähigen Synthesestrategie leicht hergestellt werden können.

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“…[24] One of the problems associated with the SPSAF procedure is the lack of rapid and reliable analysis methods for verifying the presence of all the predicted diversomers and the formation of undistorted libraries. Although several techniques have been proposed for the validation of medium arrays of mixed compounds, most of them are time-consuming [25] and need to be supported by high-technology instrumentation. [26,27] We report herein that it is possible to apply the SPSAF procedure to a symmetric diketopiperazine scaffold for the preparation of libraries of mixed amides using the isobutyl chloroformate (IBC) protocol and that the correct formation of the desired product can be monitored by quantitative GC analysis of the isobutyl alcohol (iBuOH) formed as a co-product in the coupling reaction.…”

Section: Introductionmentioning

confidence: 99%

Solution-Phase Synthesis of Mixed Amide Libraries by Simultaneous Addition of Functionalities (SPSAF) to a Diketopiperazine Tetracarboxylic Acid Scaffold Monitored by GC Analysis of Isobutyl Alcohol

et al. 2000

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A symmetric diketopiperazine scaffold 2 has been prepared in a very simple two‐step procedure from L‐aspartic acid dimethyl ester. This product (a tetracarboxylic acid equally protected at the two symmetric positions) has been employed as a template for the synthesis of mixed amide libraries in the solution phase using the SPSAF (simultaneous addition of functionalities) strategy. By judicious choice of the amines employed, it is possible to prepare parallel libraries containing hundreds of products using just a small number of different amines. We have also developed a simple method for monitoring the required conversion of the acid into amides based on an assay of the amount of iBuOH (determined by GC) formed during the coupling mediated by isobutyl chloroformate. We have observed that a conversion higher than 90% (iBuOH by GC) guarantees correct formation of the desired amides. This indirect method for assessing the conversion in a combinatorial reaction employing mixed reactants (SPSAF) can conveniently be used for the routine determination of libraries prepared in the solution phase. In a broader perspective, the present results contribute as a further step in the development of new and simple systems for monitoring the progress and evolution of combinatorial reactions

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Rapid deconvolution of combinatorial libraries using HPLC fractionation

Cited by 21 publications

References 17 publications

Mixture-Based Synthetic Combinatorial Libraries

Mixture-Based Synthetic Combinatorial Libraries

Click-Chemie: diverse chemische Funktionalität mit einer Handvoll guter Reaktionen

Solution-Phase Synthesis of Mixed Amide Libraries by Simultaneous Addition of Functionalities (SPSAF) to a Diketopiperazine Tetracarboxylic Acid Scaffold Monitored by GC Analysis of Isobutyl Alcohol

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