History of combinatorial chemistry

Furka, Árpád

doi:10.1002/ddr.430360102

Cited by 54 publications

(18 citation statements)

References 40 publications

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“…Several advances in the implementation of solid-phase library synthesis paved the way for its widespread acceptance including the spatially arrayed multipin peptide synthesis of Geysen et al, [103,104] the tea-bag method of peptide synthesis introduced by Houghten et al, [105] phage display from Smith et al, [106,107] the spot or disc synthesis developed by Frank et al, [108,109] and especially the (portion-mixing) split-and-mix solid-phase synthesis on beads introduced by Furka et al [110][111][112] and also disclosed by Houghten et al [113] (divide, couple, and recombine), and Lam et al [114][115][116] (split synthesis), and Affymax's light-directed, spatially addressable, immobilized parallel synthesis. [117] Further promoting the widespread acceptance of split-and-mix solid-phase synthesis, several identification techniques were introduced including iterative [110,118,119] and recursive [120] deconvolution, or nucleotide-, [121,222] peptide-, [123][124][125] chemical-, [126][127][128] radiofrequency-, [129,130] color-, [131] and shape-encoded [132] solid-supported libraries.…”

Section: Introduction 4139mentioning

confidence: 99%

Solution‐Phase Combinatorial Libraries: Modulating Cellular Signaling by Targeting Protein–Protein or Protein–DNA Interactions

2003

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The high-throughput synthesis and screening of compound libraries hold tremendous promise for drug discovery and powerful methods for both solid-phase and solution-phase library preparation have been introduced. The question of which approach (solution-phase versus solid-phase) is best for the preparation of chemical libraries has been replaced by which approach is most appropriate for a particular target or screen. Herein we highlight distinctions in the two approaches that might serve as useful considerations at the onset of new programs. This is followed by a more personal account of our own focus on solution-phase techniques for the preparation of libraries designed to modulate cellular signaling by targeting protein-protein or protein-DNA interactions. The screening of our libraries against a prototypical set of extracellular and intracellular targets, using a wide range of assay formats, provided the first small-molecule modulators of the protein-protein interactions studied, and a generalized approach for conducting such studies.

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Section: Introduction 4139mentioning

confidence: 99%

Solution‐Phase Combinatorial Libraries: Modulating Cellular Signaling by Targeting Protein–Protein or Protein–DNA Interactions

2003

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“…Beispiele für Fortschritte, die der Festphasensynthese von Bibliotheken zu allgemeiner Anerkennung verhalfen, sind die räumlich auflösende Multipin-Peptidsynthese nach Geysen et al, [103,104] die "Teebeutel"-Methode von Houghten et al, [105] das Phagendisplay von Smith et al [106,107] sowie die Spot-oder Disc-Synthese von Frank et al [108,109] Besondere Erwähnung verdienen auch die von Furka et al [110][111][112] eingeführte Split-und-Mix-Festphasensynthese auf Harzkügelchen ("portion-mixing"), an deren Entwicklung auch Houghten et al ("divide, couple, and recombine") [113] sowie Lam et al ("split synthesis") [114][115][116] teilhatten, und die bei Affymax entwickelte lichtgesteuerte, räumlich adressierbare, immobilisierte Parallelsynthese. [117] Neue Analysemethoden trugen zur breiten Annahme der Split-und-Mix-Festphasensynthese bei: die iterative [110,118,119] und die rekursive [120] Dekonvolution, außerdem nucleotid-, [121,122] peptid-, [123][124][125] chemische, [126][127][128] radiofrequenz-, [129,130] farb- [131] und formcodierte [132] festphasengebundene Bibliotheken.…”

Section: Hauptmerkmale Kombinatorischer Methoden In Der Flüssigphaseunclassified

Kombinatorische Flüssigphasensynthese von Bibliotheken: auf der Suche nach Modulatoren für Protein‐Protein‐ und Protein‐DNA‐Wechselwirkungen in der zellulären Signaltransduktion

2003

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Hochdurchsatzsynthese und ‐screening von Verbindungsbibliotheken haben große Erwartungen für die Wirkstoffsuche geweckt. Für die Herstellung solcher Bibliotheken an der Festphase und in Lösung sind leistungsfähige Methoden entwickelt worden. Die Synthesestrategie wird schon lange nicht mehr nach allgemeinen Erwägungen ausgewählt, sondern mit Blick auf die spezielle Fragestellung. In diesem Aufsatz beschreiben wir Unterschiede zwischen den beiden Methoden, die bei der Entwicklung neuer Programme helfen sollen. Als Beispiel beschreiben wir unsere Versuche, mithilfe von Lösungstechniken Modulatoren für zelluläre Signale durch Beeinflussung von Protein‐Protein‐ oder Protein‐DNA‐Wechselwirkungen zu identifizieren. Das Vorurteil, niedermolekulare Substanzen seien für therapeutische Intervention an solchen Zielstrukturen ungeeignet, konnten wir beim Screening unserer Bibliotheken gegen eine repräsentative Auswahl extrazellulärer und intrazellulärer Targets widerlegen: Mithilfe zahlreicher Testmethoden identifizierten wir die ersten niedermolekularen Modulatoren für Protein‐Protein‐Wechselwirkungen und erarbeiteten ein allgemeines Verfahren für derartige Untersuchungen.

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“…16'] Meutermans et al synthesized di-and tetrahydroisoquinoiines on solid phaser471 and were able to show using ion spray MS that all the predicted compounds were present in the mixture after cleavage. Another variant, which gives reliable results particularly for characterization of smaller mixtures, is the coupling of HPLC and MS.…”

Section: Characterization Of Test Substance Librariesmentioning

confidence: 99%

Combinatorial Synthesis of Small Organic Molecules

Balkenhohl¹,

Bussche-Hünnefeld²,

Lansky³

et al. 1996

Angew. Chem. Int. Ed. Engl.

733

244

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Combinatorial synthesis has developed within a few years from a laboratory curiosity to a method that is taken seriously in drug research. Rapid progress in molecular biology and the resulting ability to determine the activity of new substances extremely efficiently have led to a change in paradigm for the synthesis of test compounds: in addition to the conventional procedure of synthesizing one substance after another, new methods allowing simultaneous creation of many structurally defined substances are becoming increasingly important. A characteristic of combinatorial synthesis is that a reaction is performed with many synthetic building blocks at once—in parallel or in a mixture— rather than with just one building block. All possible combinations are formed in each step, so that a large number of products, a so‐called library, is obtained from only a few reactants. Several methods have been developed for combinatorial synthesis of small organic molecules, based on research into peptide library synthesis: single substances are produced by highly automated parallel syntheses, and special techniques enable targeted synthesis of mixtures with defined components. Many structures can be obtained by combinatorial synthesis, and the size of the libraries created ranges from a few individual compounds to many thousand substances in mixtures. This article gives an overview of the combinatorial syntheses of small organic molecules reported to date, performed both in solution and on a solid support. In addition, different techniques for identification of active compounds in mixtures are presented, together with ways to automate syntheses and process the large amounts of data produced. An overview of pionering companies active in this area is also given. The final outlook attempts to predict the future development of this exponentially growing area and the influence of this new thinking in other areas of chemistry.

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History of combinatorial chemistry

Cited by 54 publications

References 40 publications

Solution‐Phase Combinatorial Libraries: Modulating Cellular Signaling by Targeting Protein–Protein or Protein–DNA Interactions

Solution‐Phase Combinatorial Libraries: Modulating Cellular Signaling by Targeting Protein–Protein or Protein–DNA Interactions

Kombinatorische Flüssigphasensynthese von Bibliotheken: auf der Suche nach Modulatoren für Protein‐Protein‐ und Protein‐DNA‐Wechselwirkungen in der zellulären Signaltransduktion

Combinatorial Synthesis of Small Organic Molecules

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