Structural investigations of metabolites from four marine invertebrates

Each of the projects described in this thesis entails either the three-dimensional or covalent structure determination of metabolites from marine invertebrates. The first chapter reviews literature reports of three-dimensional structures of conotoxins. As more structural work in completed for contoxins, additional biological insights are revealed about the binding sites for each of the toxins. A section summarizing the biological implications of the three-dimensional contoxin structures has been included for each pharmacological class of peptides. The second chapter discusses the solution NMR structure of the recently described conotoxin known as psi-PIIIE. Though this peptide contains the same disulfide bonding framework as the µ-conotoxins, its biological activity is unique as it targets the acetylcholine gated ion channel rather than the voltage gated sodium channel. Furthermore, inhibition of the acetylcholine gated ion channel by psi-PIIIE occurs by a different mechanism than the psi-conotoxins, demonstrating that the psi-conotoxin represent a novel pharmacological class of conotoxins. Determination of the three-dimensional structure of psi-PIIIE represents an important initial step in understanding what structural components of the peptides are required for this unique activity. Chapter 3 and 4 describe the isolation and structure determination of several nucleic acid derivatives from the ascidian Didemnum voeltzkowi and the sponge Amphimedon viridis. The covalent structure of nucleic acids is difficult to determine using only NMR spectroscopy, and mass spectroscopic and synthetic techniques were also employed in the complete structure determination of these metabolites. Chapter 5 discusses the isolation of a novel blue pigment from the ascidian Eudistoma olivaceum and includes evidence supporting a structural proposal for the metabolite. Purification of the compound required extensive investigations of the solubility and stability of the compound, which in turn yielded several important clues to the structure of the molecule. The results of chemical degradation experiments on the natural product and numerous spectroscopic techniques are also described, providing considerable evidence for the proposed structure.