This proposal outline a strategy to develop libraries that mimic the natural product Dazonamide A. Natural products have traditionally been used as ligands to elucidate the proteins to which they bind. Because a natural product alters a protein's ability to function, it can be used to decipher the cellular function of that protein. In a case where the protein target is unknown, a number of natural product mimics help elucidate that protein, and determining its cellular function is expedited. Therefore, combinatorial libraries of natural product-like molecules are needed as powerful tools in determining protein targets and their cellular function. Diazonamide A is a cytotoxic natural product whose biological target is unknown. Diazonamide A will be disconnected as a peptide containing five amino acids. Three key transformations; oxazole formation, a Heck reaction and a Stille coupling modify these five amino acids. Because both natural and unnatural amino acids are readily available, the synthetic strategy readily lends itself to combinatorial libraries. Varying the amino acids and the three transformations will create a vast number of libraries. Each library contains compounds which mimic a portion or all of Diazonamide A. These libraries will help elucidate the protein target of Diazonamide A and determine the cellular function of that protein. In the long term, this new ligand protein system will be used to manipulate cellular activities.
