The salicylihalamides and lobatiamides are two new families of natural products that exhibit promising antitumor activity. These molecules share a core structure and have a novel mode of action that makes them excellent candidates for combination drug therapy with known antitumor compounds. For combination drug therapy to be possible, there must be significant quantities of the desired agents available. Furthermore, the natural products isolated may not be optimized for treating a given type of cancer. To optimize activity, structure/activity relationships (SAR) need to be explored. In order to begin SAR work though, an initial hypothesis regarding some aspect of the molecules' biological activity needs to be identified and then addressed. In this proposal, simulated annealing of truncated versions of the natural products has been conducted. Multidimensional graphical analysis of the resulting conformations revealed a common structural motif of the conserved core. This structural motif is hypothesized to be the three dimensional structure of the pharmacophore. Analogs that will test the accuracy of this proposed pharmacophore have been designed. These analogs remove functionalities not part of the pharmacophore and constrain the molecule to the three dimensional conformation of the proposed pharmacophore. Concise and convergent syntheses of these analogs and of salicylihalamide A are outlined. The methodologies employed allow for both structural variations as well as variations in the absolute and relative stereochemistries of the products. These synthetic routes will supply valuable material for future SAR testing to aid the development of antitumor agents.
