New antifungal and cytotoxic cyclic peptides and studies of the bacterial symbionts of lithistid sponges

Chapter 1 of this dissertation introduces the biology, taxonomy and chemistry of sponges of the order Lithistida. The unique skeletal characteristics currently used to classify this polyphyletic group are explained, and many of the natural products discovered from lithistid sponges are reviewed.;Chapter 2 describes the isolation and structural elucidation using spectroscopic methods of theonegramide (44), a bicyclic glycopeptide from Theonella swinhoei. The absolute stereochemistry of 44 was determined using chiral GCMS. The structural elucidation of theonegramide by 2-D NMR was initially hampered by the behavior of the peptide in most solvents. The problems encountered and the probable conformational changes induced by different solvents of theonegramide and a similar bicyclic peptide, theonellamide F (23), are discussed.;Chapter 3 is a reprint describing the structural elucidation of microsclerodermins A and B from the deep water sponge Microscleroderma sp. Microsclerodermins A and B contain several unprecedented amino acids which include a tetra-substituted pyrollidone and a tris-hydroxy-;Chapter 4 elucidates the structure of three homologous glycopeptidolipids, aciculitins A-C (49-51), from the lithistid sponge Aciculites orientalis. The aciculitins are the first glycopeptidolipids to be reported from a marine source and are cytotoxic to a human colon tumor (116) cell line. Prior studies of A. orientalis in this laboratory yielded aciculitamides A and B (57, 58) which were artifacts of the isolation procedure; previously proposed structures of 57 and 58 were tentative. Through chemical interconversion of aciculitin B and interpretation of spectral data, the correct structures of the aciculitamides have been established.;Chapter 5 addresses the subject of symbiosis and the origins of secondary metabolites in the lithistid sponge Theonella swinhoei. T. swinhoei is unusual because it contains populations of three distinct types of bacterial symbionts, each of which is described in detail. It has been suggested that many of the natural products found in T. swinhoei are produced by cyanobacterial symbionts. From Palauan specimens of T. swinhoei that contain the macrolide swinholide A (1) and a peptide similar to theonegramide (44), the three bacterial types and the sponge cells were separated from one another by differential centrifugation and identified by TEM. The cells were extracted and analyzed by three methods (UV and NMR spectroscopies and HPLC) to locate swinholide A in the mixed population of heterotrophic unicellular bacteria, and the peptide in the non-photosynthetic, filamentous bacterial symbiont. The sponge cells and cyanobacteria were devoid of these natural products. These results and their implications are discussed.