Antitumor agents

NP-based drug discovery is not generally limited to specific disease areas, but NP have been of particular importance in the development of drugs against infectious diseases and cancer. Or own work includes several examples of NP leads that could be of therapeutic interest in either of these areas (see also Antibacterial Agents). In general, the initial aim of the work is the development of an efficient total synthesis of the corresponding NP followed by analog synthesis for structure-activity-relationship (SAR) studies. In this context, the de novo chemical synthesis of NP analogs provides access to areas of structural space that could not be explored based on semisynthesis or microbiological approaches. As exemplified by our work on zampanolide analogs, this can then also lead to biologically active analogs with reduced structural complexity (relative to the parent NP). At the same time, the total synthesis of natural zampanolide enabled structural studies on zampanolide/tubulin complexes that have provided fundamental new insights into the mechanism of tubulin assembly and on how this process can be promoted by certain NPs. Likewise, the synthesis of analogs of the fungal metabolite fumitremorgin C has enabled the first high resolution structure of the liganded drug efflux transporter ABCG2 (in collaboration with the group of Prof. Kaspar Locher at the Department of Biology of the ETH Zürich).