Development of pyrimidine- and purine bioisosters

In dieser Arbeit wird die Darstellung einer Gruppe von neuen Purin- und Pyrimidin Bioisosteren diskutiert. Der systematische Name von Purin lautet Imidazo[4,5-d]pyrimidine. Als Nucleosidbausteine finden vor allem die am Imidazolring glycosylierten N9-Purinylnucleoside Anwendung. Beim Einbau in Oligonucleotide wird die klassische Watson-Crick Basenpaarung A-U(T), G-C beobachtet. In dieser Studie wurden am N1 glycosylierte Purinylnucleosidbausteine hergestellt. In dieser am Pyrimidinstickstoff glycosylierten Verbindungsklasse sind neben der klassischen Watson-Crick-Basenpaarung auch weitere Wasserstoffbrückenbindungen zum unsubstituierten Imidazolteil des Nucleosides vorstellbar. Im zweiten Teil wird die Synthese eines neuartigen, flexiblen Purinbioisosters diskutiert, das sich als glycosyliertes Dihetarylamin beschreiben lässt. Dabei werden die charakteristischen Erkennungselemente für sowohl Purine alsauch für Pyrimidine beibehalten. Die Synthese des zugrunde liegenden Dihetarylamins erfolgt entweder durch eine palladiumkatalysierte Aminierungsreaktion oder durch reduktive Entschwefelung des 3-cyclischen Azaphenothiazin Vorläufers.This thesis describes the development of a series of novel pyrimidine- and purine bioisosters. Systematically purines are called imidazo[4,5-d]pyrimidine. In nucleoside chemistry the synthesis and incorporation of N9-purinylnucleoside - glycosylated at the imidazole nitrogen atom is well established. In these cases the classical Watson-Crick base pairing A-U (T), G-C is observed. This study deals with the chemical synthesis of N1-glycosylated purinylnucleoside building blocks. In this substance-class, bearing the sugar moiety at the pyrimidine nitrogen, beside the classical Watson-Crick-base pairing additional hydrogen bridges to the unsubstituted imidazole moiety are conceivable. The second part of this thesis deals with the development and synthesis of a novel, flexible purine bioisoster, which also can be described as a glycosylated dihetaryl amine derivative. In this novel class the typical purine and pyrimidine recognition elements are retained. The proposed dihetaryl amines may either be obtained by palladium catalysed amination reaction or via reductive desulfurination of the 3-cyclic azaphenothiazin precursor

Substituted 2-aminothiazoles are exceptional inhibitors of neuronal degeneration in tau-driven models of Alzheimer's disease

A novel series of 2-aminothiazoles with strong protection in an Alzheimer's disease (AD) model comprising tau-induced neuronal toxicity is disclosed. These derivatives can be synthesized in one-pot and a small SAR of the substitution within these series afforded several compounds that counteracted tau-induced cell toxicity at nanomolar concentrations. These congeners therefore have strong potential as possible treatment for Alzheimer's disease and other related tauopathies.status: publishe