Chirale Allenylcarbamate, Darstellung und Verwendung in der enantioselektiven Synthese

Im ersten Teil der Dissertation wurde die (-)-Spartein-vermittelte Deprotonierung von verschiedenen 2-Akinylcarbamaten untersucht. Hierbei zeigt es sich, daß hohe Enantiomerenanreicherung nur durch eine selektive Kristallisation eines Diastereomeres der beiden konfigurativ labilen Lithium-Carbanion-Komplexe zu chiralen Allenyl- und Alkinylcarbamten nach der elektrophilen Substitution führt. Der stereochemische Verlauf der Reaktion wurde zweifelsfrei aufgeklärt. Durch eine Umwandlung der 2 ten Art kristallisiert selektiv der (S)-konfigurierte Lithium-Carbanion-Komplex ) aus. Dieser wird aus dem Gleichgewicht entfernt und durch Epimerisierung nachgebildet, so daß sich das hochenantiomerenangereicherte Lithiumorganyl im Kristallisat anreichert. Die anschließende stereospezifische Substitution führt zu hochenantiomerenangereicherten Aklinylcarbamten bzw. im Falle einer Transmetallierung C1Ti(Oi-Pr) 3 zu chiralen Allenylcarbamaten

Identification of pyrazolopyridazinones as PDEδ inhibitors

The prenyl-binding protein PDEδ is crucial for the plasma membrane localization of prenylated Ras. Recently, we have reported that the small-molecule Deltarasin binds to the prenyl-binding pocket of PDEδ, and impairs Ras enrichment at the plasma membrane, thereby affecting the proliferation of KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, using structure-based compound design, we have now identified pyrazolopyridazinones as a novel, unrelated chemotype that binds to the prenyl-binding pocket of PDEδ with high affinity, thereby displacing prenylated Ras proteins in cells. Our results show that the new PDEδ inhibitor, named Deltazinone 1, is highly selective, exhibits less unspecific cytotoxicity than the previously reported Deltarasin and demonstrates a high correlation with the phenotypic effect of PDEδ knockdown in a set of human pancreatic cancer cell lines

Structure Guided Design and Kinetic Analysis of Highly Potent Benzimidazole Inhibitors Targeting the PDEδ Prenyl Binding Site

K-Ras is one of the most frequently mutated signal transducing human oncogenes. Ras signaling activity requires correct cellular localization of the GTPase. The spatial organization of K-Ras is controlled by the prenyl binding protein PDEδ, which enhances Ras diffusion in the cytosol. Inhibition of the Ras–PDEδ interaction by small molecules impairs Ras localization and signaling. Here we describe in detail the identification and structure guided development of Ras–PDEδ inhibitors targeting the farnesyl binding pocket of PDEδ with nanomolar affinity. We report kinetic data that characterize the binding of the most potent small molecule ligands to PDEδ and prove their binding to endogenous PDEδ in cell lysates. The PDEδ inhibitors provide promising starting points for the establishment of new drug discovery programs aimed at cancers harboring oncogenic K-Ras