Natural products have served as an effective source of drugs and drug leads throughout history. In part, this is due to the unique structures and the well-defined stereochemistry found in these compounds which allow them to interact selectively with biological target molecules. Unfortunately, most natural products themselves are not suitable for administration as drugs. Chemical synthesis, however, can be employed to study and address some of these shortcomings through manipulation of pharmacological properties, structure activity relationship studies, and the preparation of compounds for mechanistic studies by molecular biologists.
In this thesis, an overview of the role of natural products is presented in order to set the stage for two current drug discovery and development studies which are based on natural product leads. The first project involves the development of a library of curcumin analogues. This effort was initially directed simply at the development of more effective anticancer agents based on the curcumin scaffold. As the project evolved, however, it became clear that a fairly comprehensive library of structurally diverse analogues may be useful for the identification of new leads which could affect other disease states or biological targets. The second project involves the isolation and development of novel compounds for the treatment of leishmaniasis, a parasitic disease. In this case, a short synthetic route was developed to give access to the scaffold of the natural products isolated from a Mexican plant. Based on this strategy, a number of analogues have been produced which have helped to define the structure-activity relationship of this class of molecules.