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Chemistry of natural products
From this figure it is obvious that several different strategies for chemotherapy are known. A particularly successful mode of action is the interaction of small molecules such as Epothilon, Taxol or certain Vinca Alkaloids with microtubuli and a number of highly successful anticancer drugs are based on this antimitotic concept. Tryprostatin derivatives (they belong to a family of fungal metabolites) are a relatively new class of compounds showing antimitotic properties, although their precise mode of action is not yet known. Besides these antimitotic properties, several tryprostatin derivatives have been found to overcome multidrug resistance, a serious problem in current cancer chemotherapy. Given this profile, derivatives of tryprostatin are extremely valuable candidates for the search of new chemotherapeutics.
Fig. 1: Selection of common chemotherapeutics and their modes of action.
The search for new chemotherapeutics starts generally with the natural product and leads in most cases to non natural analogs thereof as drug candidates with Taxol and Epothilon being excellent examples for this strategy (derivatives of Taxol are marketed from different companies and a derivative of Epothilon A will most likely be marketed soon by Schering). This discovery process demands efficient synthetic methodologies for the assembly of natural product scaffolds and the preparation of close analogs. In this context we are going to establish a general synthetic scheme to heterocyclic natural product scaffolds and apply it to the synthesis of tryprostatin analogs. Our synthetic approach is fundamentally new and is suitable for the preparation of structurally diverse libraries of these natural products, which will be used for screening of anticancer activity.
27.06.2009 16:53
