Synthesis of Peptidic, Natural Product-inspired, and Heterocyclic Molecules as Biological Probes

The first section of this thesis describes the solid phase peptide synthesis of scotophobin, a small peptide thought to be responsible for the transference of a learned response between mammals, and several related peptides. The synthetic peptides were tested against an array of G protein-coupled receptors. Although interesting activity was observed, these studies failed to provide closure to the storied past of scotophobin. We were able to demonstrate that the small peptide possesses in vitro activity.\ud The second section describes the optimization of the thiol-mediated epoxide opening and intramolecular aldol reaction of epoxyketones. This methodology provided access to a variety of densely functionalized bicyclo[3.3.1]non-3-en-2-ones in moderate to good yield (64-88%). The newly synthesized bicyclo[3.3.1]non-3-en-2-ones were shown by a ChemGPS-NP analysis to occupy novel regions of chemical space. In addition, they exhibited moderate activity in several assays. \ud The third section describes our efforts toward the total synthesis of chrysophaentin A. Although the synthesis of the natural product has yet to be achieved, the convergent synthesis of the monomeric C1-C16 tetraphenol of chrysophaentin A was completed in 10 steps (longest linear sequence) and 24% overall yield. The collaborative biological evaluation of two monomeric chrysophaentin A fragments revealed that they retained the potent antimicrobial activity of the parent natural product. \ud The final section of this thesis describes the synthesis of three peptide-like inhibitors as well as several non-peptidic small-molecule inhibitors of botulinum neurotoxin serotype A light chain (BoNT/A LC). In collaborative work, all three peptidic inhibitors were found to possess sub-µM activity. X-ray crystallography was used to document the binding mode of one of the peptidic inhibitors on BoNT/A LC.\u