PhD defence A. Boltjes

Development and application of novel scaffolds in drug discovery

The research André Boltjes described in his thesis covers the application of MCR methodologies aimed at expansion of the scaffold library and implementation of these scaffolds for the development of pharmaceutical relevant, drug-like compounds and diagnostic probes. Scaffold design was achieved either by clever application of bifunctional MCR components, or implementation of underexplored starting materials. Applicability of the scaffolds was found to be quite broad, covering biological targets such as anti-cancer and kinases, application as a new class of MRI contrast agents and peptidomimetics for yet to be discovered targets. Moreover, the thorough review of one the youngest MCRs, the GBB-3CR, revealed affinity of the associated GBB-scaffold for a wide variety of biological targets. This scaffold is still underexplored, thus exhibits high potential for drug discovery. Additionally Boltjes worked on the improvement of IMCRs by addressing limitations in availability and/or problematic application of isocyanides. The approach was demonstrated through the example of the synthesis of praziquantel and covers an important procedure of both a MCR approach to synthesize a marketed drug in less reaction steps into a more optimized reaction, as well as in situ formation of the isocyanide compound through readily available formamides. Overall the MCR scaffold design described in this thesis was successfully linked by Boltjes to new potential targets and the resulting compounds were applied as drug-like compounds and introduced beyond the scope of drug discovery

Promotores: Prof.dr. A.S.S. Dömling and Prof.dr. F.J. Dekker