DIAZONAMIDE SYNTHESIS:A MODEL FOR PEPTIDE METAMORPHOSIS

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Diazonamide A is a polycyclic secondary metabolite which potently inhibits the growth of a transformed human cell line in vitro. The molecular basis for this activity is unknown. This research seeks to provide synthetic resources necessary for probing diazonamide function and, simultaneously, those of general utility in alternate small molecule discovery programs. The diazonamide structure can be viewed either as a collection of attachable components or as an extensively modified linear pentapeptide. In line with the former, strategies are outlined to assemble the diazonamide skeleton from four fragments including: two alpha-amino acids, a 2-ethynylphenol, and serotonin. A Heck endocyclization / ring-contracting rearrangement sequence installs the C10 quaternary center in diazonamide segment 71. The last fragment (serotonin) is incorporated and the natural framework is completed via orthophenolic coupling to form the C16/C18 biaryl linkage. Tagging for biochemical analysis is outlined for a series of ascending intermediates. Three components and a partial sequence used in diazonamide synthesis form the basis of heterotriarylethylene libraries (103 - 106 members) built using both combinatorial and parallel synthesis techniques. Diazonamides are bioactive metabolites derived from peptides via chemical modification. A conceptually similar, but completely synthetic, strategy is proposed to access complex natural product-like molecules randomly from parallel libraries of short oligopeptides. Five to seven residue natural / artificial hybrid oligopeptides are synthesized on the surface of glass through a photolabile linker. Four types of chemical modifications are explored on intact peptides 1) alkynylation and vinylation with functionalized triflones 2) dehydrative cyclization of serine and cysteine motifs to oxazolines and thiazolines, respectively 3) oxidative intrachain coupling of aromatic residues and 4) metathetical cyclization between proximate olefins. Multiple modifications run in sequence on parallel libraries of pure oligopeptides followed by photorelease is a renewable screening resource for identifying small molecules with therapeutic effects on human cells.