Research

Research in the Altmann group is centered on the chemical synthesis of pharmaceutically relevant natural products/natural product analogs and their biological evaluation.

Natural products (NPs) represent a unique and highly prolific source of lead structures for drug discovery and development, with a large fraction of currently marketed drugs (between 25% and 50%, depending on the source of the analysis) being derived from a natural product.

While NP-based lead optimization traditionally has relied on the semi-synthetic derivatization of material obtained from natural sources, chemical synthesis has now assumed a more prominent (and ever expanding) role in drug discovery. This is due to both the dramatic improvements that have occurred in synthetic methodology, but also the fact that a growing number of interesting NPs is available from the natural source only in low quantities (especially when obtained from marine organisms). In such cases chemical synthesis often represents the only means to enable comprehensive biological studies. At the same time there is a growing recognition that the chemistry developed in the course of the total synthesis of a NP provides the basis for structure-activity-relationship (SAR) studies in areas of structural space that are not accessible either through semi-synthesis or the genetic manipulation of producer organisms. The full exploration of structural space around a NP, however, is important not only for the basic understanding of the relationship between molecular structure and biological activity, but eventually it may also lead to highly active, but less complex analogs and even to completely new scaffolds or chemotypes for interference with a given pharmacological target. Within this framework, the major objectives of our work are (i) the total synthesis of biologically active natural products and their profiling; (ii) the elucidation of the structural requirements for biological activity of individual natural products; (iii) the assessment of opportunities for structural simplification and molecular editing of complex natural products, in order to produce simplified analogs and/or new chemotypes for interference with a given pharmacological target; and (iv) in selected cases, the elucidation of the mechanism of action of biologically active natural products. Ultimately, all of these efforts aim at the identification of new leads for drug discovery or potential drug candidates. The work in the group is largely chemistry-based, while biological questions are addressed in collaborations with appropriate partners.

Our work so far has mainly (but not exclusively) focused on potential lead structures for anticancer drug discovery, such as the microtubule-stabilizing agents epothilones, peloruside A, and zampanolide, and the kinase inhibitor L-783277. While cancer will continue to be one of our focus areas, more recent activities also include natural products related to infectious diseases. In particular, we will focus on natural product leads that could be of relevance for the discovery of new drugs for the treatment of tuberculosis. This work will be carried out within the framework of the EU FP7 program “More Medicines for Tuberculosis” (MM4TB). In addition, we are currently initiating medicinal chemistry programs for the discovery of inhibitors of selected biological transporters, based on natural product as well as synthetic leads. These programs will be conducted within the framework of the SNF-sponsored National Competence Center for Research (NCCR) “Transcure”. Work on MM4TB and Transcure related target structures has just been initiated and therefore is not (yet) discussed on this website.

· Antitumoral natural products

· Other projects