Chapter 1. The history of the cyclic peptides was briefly introduced. The syntheses of cyclic peptides via solid-phase strategy as well as solution-phase strategy were also discussed. The aims of this research are listed at the end of this chapter.

Chapter 2 and 3. Seven Sansalvamide A derivatives have been synthesized and sixty-four Sansalvamide A peptide derivatives were tested by using ³H thymidine inhibition assays in two pancreatic cancer cell lines (PL45 and BxPC-3) to evaluate their Structure- Activity Relationships (SAR). Six compounds show greater cytotoxicity against pancreatic cancer cell lines than the commonly used drug, 5-FU, and demonstrate potency on par with treatments used for other cancers. Four compounds have low micromolar IC50 values against BxPC-3 and PL45 and are ∼20 fold more active than the parent natural product Sansalvamide A peptide (San A). SAR studies show the inclusion of a single N-methyl and/or

D

-amino acid appears to be critical for presenting the active conformation of the five San A peptide derivatives to their biological target(s).

Chapter 4. Holliday junctions (HJs) are formed as transient DNA intermediates during site-specific and homologous recombination. Trapping HJs leads to bacterial cell death by preventing proper segregation of the resulting interlinked chromosomes, making them ideal targets for potential new antibiotics. Macrocyclic peptides designed to trap this intermediate were synthesized in the hopes of designing compounds capable of antibacterial activity. Ten macrocycles, both hexameric and octameric peptides, proved they were capable of trapping HJs in vitro. Those macrocycles containing tyrosine residues proved most effective. These data demonstrate that C-2 symmetrical macrocycles offer excellent synthetic targets for the development of novel antibiotic agents. Furthermore, the active compounds provide valuable tools for probing different pathways of recombinational exchange.

Chapter 5. Triostin A is a bicyclic octadepsipeptide, a member of the quinoxaline family of antitumor agents, and can efficiently block both transcription and replication via specific binding at GC positions in the minor groove of dsDNA. Its derivative, Azatandem, was shown to possess antitumor potency. Our efforts to improve the preparation of such derivatives have provided a unique synthetic approach via use of the KAHA (α- Ketoacid-Hydroxylamine) ligation reaction to furnish the bicyclic core. This proposed strategy will provide structurally diverse Triostin A derivatives in an efficient manner.