Solid-Supported Reagent Strategies for Rapid Purification of Combinatorial Synthesis Products

and, R. John Booth; Hodges, John C.

doi:10.1021/ar970311n

Cited by 174 publications

(57 citation statements)

References 24 publications

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“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] A complement to adapting solution-phase chemistry to polymersupported combinatorial synthesis is the development of protocols for solution-phase combinatorial synthesis. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] A number of approaches have been introduced for this purpose including dynamic combinatorial chemistry, [32,33] soluble polymer-supported combinatorial synthesis (pioneered by Janda et al), [34][35][36][37][38] fluorous-phase synthesis (FPS) [39,40] and other tagging strategies, [41] precipitation techniques, [42][43][44][45] and resinbound, [46][47][48]…”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] A number of approaches have been introduced for this purpose including dynamic combinatorial chemistry, [32,33] soluble polymer-supported combinatorial synthesis (pioneered by Janda et al), [34][35][36][37][38] fluorous-phase synthesis (FPS) [39,40] and other tagging strategies, [41] precipitation techniques, [42][43][44][45] and resinbound, [46][47][48][49][50][51][52] soluble polymer-bound, [53] and fluorous-phase bound [30,40] catalysts, reagents, or scavenging reagents. [46][47][48][49][50][51][52] Preceding this work, we introduced a simple approach that permits the multistep solution-phase synthesis of chemical libraries employing liquid-liquid and liquid-solid (ionexchange resin) extractions to remove residual starti...…”

Section: Introductionmentioning

confidence: 99%

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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question of which approach (solution-phase versus solid-phase) is best for the preparation of chemical libraries has been replaced by which approach is most appropriate for a particular target or screen.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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2003

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“…Die Ligandenbindung induziert eine Dimerisierung oder Oligomerisierung, und dies ermöglicht die Wechselwirkung (Dimerisierung) und Aktivierung (Kreuzphosphorylierung) nichtkovalent assoziierter Tyrosinkinasen (Januskinasen, JAKs, Abbildung 11). [47,71,188,318] Im Gegenzug phosphorylieren die aktivierten JAKs Tyrosinreste cytoplasmatischer Domänen des Rezeptors, die dann Signalproteine wie die STATs (Signal Transducers and Activators of Transcription) aktivieren. [187,188] [319,320] Durch Röntgenstruktur-analyse des Peptid-Rezeptor-Komplexes [321] konnte im Detail geklärt werden, wie zwei Moleküle des Peptids das EBP (EPO-bindendes Protein, die extrazelluläre Domäne von EPOR) dimerisieren (Abbildung 12 und 13): [322] Der Komplex besteht aus einem Peptiddimer, das von zwei Molekülen EBP flankiert ist; es weist eine verblüffende Strukturhomologie mit dem Wachstumshormon-und dem Prolactinrezeptor auf.…”

Section: Epo/epor: Agonisten Aus Antagonistenunclassified

“…[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] Zu diesem Zweck wurden Methoden wie die dynamische kombinatorische Chemie, [32,33] die polymergestützte kombinatorische Synthese in Flüssigphase (zuerst vorgestellt von Janda et al [34][35][36][37][38] ), die fluorige Synthese (FPS) [39,40] und andere Markierungsstrategien [41] sowie Fällungstechniken [42][43][44][45] eingeführt. Auch harzgebundene, [46][47][48][49][50][51][52] lösliche polymergebundene [53] und fluorphasengebundene [30,40] Katalysatoren, Reagentien oder Spülreagentien [46][47][48][49][50][51][52] wurden verwendet. In ersten Arbeiten führten wir ein einfaches Verfahren zur mehrstufigen Flüssigphasensynthese von chemischen Bibliotheken ein: Durch Flüssig-flüssig-und Flüssig-fest-Extraktionen (mit Ion...…”

Section: Introductionunclassified

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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“…9,10) The 1,3-dipolar cycloaddition of polymer-bound munchnones with a variety of alkynes has been developed to produce a library of up to 10 8 different pyrroles.…”

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confidence: 99%

Convenient Synthesis of 4-Trifluoromethyl-Substituted Imidazole Derivatives.

Kawase

Saito

Kurihara

2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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The synthesis of trifluoromethyl (CF 3 )-substituted heteroaromatic compounds has received considerable interest since many of them sometimes exhibit unique chemical, physiological or physical properties.1) The search for a simple and efficient access to heteroaromatic compounds with a CF 3 group at a specific position is an important goal in this area. 2)Imidazole and its derivatives are an important class of heterocycles and many naturally occurring imidazoles are known to possess biological activity.3) The imidazole nucleus is also a major component of a variety of drugs such as angiotensin II receptor antagonists, oral antiinflammatory agents, protein kinase inhibitors and fungisides.4) Furthermore, CF 3 -substituted imidazoles have found applications in the medicinal and agrochemical fields. 5)In the course of our studies on the reactivities of mesoionic 1,3-oxazolium-5-olates, 6) we have focused on 4-trifluoroacetyl-1,3-oxazolium-5-olates (1) as useful synthons for CF 3 -substituted heterocycles. 7)Compound 1 could easily be prepared from N-acyl-Nalkylglycines 2 with trifluoroacetic anhydride (TFAA). 8) In general, the mesoionic 1,3-oxazolium-5-olates are too unstable to be isolated and are utilized in situ.6) However, compound 1 with a 4-trifluoroacetyl group can be isolated and stored for several months. It is reported that compound 1 showed high reactivity towards nucleophilic reagents such as H 2 O, EtOH, and AcOH, bringing about ring-opening reactions.8) These reactions occur via an initial attack of a nucleophile on the C-5 position of the ring. 7d) We have examined the reactions of 1 with N-nucleophiles such as amidines, 7a) ammonia, 7b) hydrazines, 7c) and aminomalonate. 7e) In principle, nucleophilic reagents can be expected to be added to one of the three electrophilic centers at C-2, C-5, and COCF 3 in 1.Combinatorial chemistry has emerged as a powerful tool for accelerating the synthesis and screening of diverse collections of molecules.9,10) The 1,3-dipolar cycloaddition of polymer-bound munchnones with a variety of alkynes has been developed to produce a library of up to 10 8 different pyrroles.11) The solid-phase synthesis of non-fluorinated imidazoles is reported to utilize a munchnone cycloaddition to aryltosylimines. 12) Recently, the reaction of 1 with amidines 7a) has also been applied to a combinatorial solidphase synthesis to prepare a library of two hundred 5-trifluoroacetylimidazoles by Hamper et al.13) Thus, munchnone chemistries are suitable to develop new synthesis in combinatorial chemistry.We now present a full account of the reactions of 1 with ammonia 7b) and a new synthesis of 4-trifluoromethylimidazoles (4). Results and DiscussionThe 4-trifluoroacetyl-1,3-oxazolium-5-olates (1a-d) required for this study were prepared by the reaction of N-acyl-N-alkylglycines (2a-d) with TFAA. The derivatives employed in this study, along with the products (3a-i and 4a-i), are summarized in Chart 1. Table 1 shows the results when 4-trifluoroacetyl-1,3-oxazolium-5-olate (1a) was allowed ...

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Solid-Supported Reagent Strategies for Rapid Purification of Combinatorial Synthesis Products

Cited by 174 publications

References 24 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

Convenient Synthesis of 4-Trifluoromethyl-Substituted Imidazole Derivatives.

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