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

Abstract

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.

Building a Macrocyclic Toolbox from C‐Linked Carbohydrates Identifies Antiangiogenesis Agents from Zebrafish Assay

“…In continuation of our interest in building a glyco‐based macrocyclic toolbox to search for modulators of protein–protein,1,2 DNA/RNA–protein3 interactions and the dissectors of signalling pathways,4 herein, we outline another strategy to obtain a different family of glycohybrids 5–10. As briefly discussed in our recent papers,11,12 the need to access compounds that bear a closer resemblance to natural products in terms of their 3D architecture and the presence of several chiral functional groups is growing constantly 13–15.…”

Multicomponent Assembly of Highly Substituted Indoles by Dual Palladium‐Catalyzed Coupling Reactions

“…Multicomponent reactions are advantageous in that they provide expedient methods for the construction of complex structures, minimize synthetic steps, and use relatively simple starting materials. [10] The overall one-pot three-step multicomponent assembly reported herein is illustrated in Scheme 1.Reaction optimization established that the use of the dppf ligand (1,1'-bis(diphenylphosphanyl)ferrocene; Scheme 2) and Cs 2 CO 3 as base (Table 1, entry 4) gave the best yields. When Xphos, tBuXphos, and Xantphos (entries 1, 2, and 3, respectively) were used the product was obtained, albeit in lower yields, whereas PPh 3 (entry 5) and PtBu 3 (entry 6) did not promote the reaction.…”

“…Multicomponent reactions are advantageous in that they provide expedient methods for the construction of complex structures, minimize synthetic steps, and use relatively simple starting materials. [10] The overall one-pot three-step multicomponent assembly reported herein is illustrated in Scheme 1.…”

“…[13] In experiment 1, the use of a strong base (NaHMDS) favors enolate formation; although Buchwald-Hartwig coupling occurred (to form 9), subsequent enolate coupling (to form 10) failed. In experiment 2, initial enolate generation and coupling occurred but subsequent amine addition did not give the Buchwald-Hartwig product (10). For experiment 3 the attempted enolate coupling using optimized reaction conditions (that is, with a weaker base) gave only a trace amount of desired product; the major product (12) formed arose from dimerization of cyclopentanone.…”

A Modular Approach to Build Macrocyclic Diversity in Aminoindoline Scaffolds Identifies Antiangiogenesis Agents from a Zebrafish Assay

“…With the goal of expanding the currently accepted chemical space to search for small molecule modulators of protein-protein [1][2][3] and DNA/RNA-protein [4] interactions and signaling pathways, [5,6] the past few years have seen a growing interest in accessing small molecules [7][8][9] that are more natural product like, and many of these small molecules are obtained through the inspiration of bioactive natural products. [10][11][12] Traditionally, small molecules that are broadly available to the medicinal chemistry community for early biological evaluation are rich in sp 2 character, and in general, they lack the features that are commonly found in bioactive natural products.…”