| The protein phosphatases are enzymes that act in concert with kinases to regulate a large number of intracellular signaling cascades. Two of the key types of serine/threonine protein phosphatases are PP1 and PP2A, which can be differentiated pharmacologically from the other phosphatases, because they are selectively inhibited by a number of natural products, such as tautomycin and okadaic acid. The goal of designing and synthesizing derivatives of the natural product inhibitors of the protein phosphatases in order to discover highly selective inhibitors of PP1 and PP2A that can delineate the respective cellular functions between the two enzymes has been objective of investigation for some time.; In order determine the parts of the existing pharmacophore for protein phosphatases inhibition that are necessary for controlling selectivity for PP1 and PP2A inhibition, a number of molecular modeling studies were initiated. First, conformational analyses of the acidic group of the pharmacophore in a number of full-sized tautomycin derivatives revealed that this portion of the pharmacophore accommodated significant variation without effecting selectivity for protein phosphatase inhibition. Second, a new model for the tautomycin-PP1 complex was constructed based upon the okadaic acid-PP1 X-ray complex, and this model rationalized the biological activity of a series of tautomycin analogs with the spiroketal excised. Third, structure-based design was used to create new truncated analogs of okadaic acid that, according to our model, could recapitulate the binding of the parent natural product and conserve the important contacts to the respective domains of PP1.; Synthetic studies were initiated to prepare the truncated okadaic acid analogs for determination of their IC50 values for inhibition of PP1 and PP2A. During the course of these investigations, a new cuprate system was developed for opening epoxides with 2,2-disubstituted olefins. Also, the reductive coupling of vinyllithiums with silyl tosylhydrazones was extended to procure a synthetic intermediate with the necessary backbone for the okadaic acid analogs. Progress toward all of these targets has been made across three synthetic routes, and the goal of an efficient preparation of the okadaic acid analogs via a common synthetic intermediate is now within reach. |
