PhD

dissertationMarine organisms have been shown to produce a wide variety of biologically active secondary metabolites, often without precedent among known terrestrial natural products. As part of a continuing program to screen Fijian marine invertebrates for novel bioactive compounds, two organisms, the sponge Jaspis johnstoni and the didemnid tunicate Lissoclinum patella, have been investigated. Isolation of the active constituents of these organisms was directed by various bioassays and utilized standard chromatographic techniques. The structures were solved using a variety of spectroscopic methods with the major emphasis placed on high field two-dimensional nuclear magnetic resonance (2D NMR), single crystal x-ray diffraction and tandem mass spectrometry. Several of the structure proofs also relied heavily on analysis of key degradation products. The major active metabolite in the Jaspis sponge was found to be a novel compound of mixed peptide/polyketide biosynthesis called jaspamide. Jaspamide is a potent natural insecticide and antifungal agent with moderate cytotoxicity. The 7-deazapurine nucleosides toyocamycin and 5-(methoxycarbonyl)tubercidin and the corresponding aglycones were also isolated. Previous work has shown L. patella, collected from Palau and Australia, to produce a family of cytotoxic, cyclic peptides all containing a thiazole and usually an oxazoline amino acid. In contrast, the Fijian tunicate contained a series of thiazole-containing macrolides, the patellazoles, and a group of modified, thiazoline-containing cyclic peptides, the patellins. The patellazoles were extremely effective antitumor compounds in the National Cancer Institute's human cell line protocol with mean IC(50)s of 10{-3} to less than 10{-6}mu-g/mL. They also exhibited potent antiviral activity in vitro but were too toxic for in vivo use. The structures were solved primarily using NMR techniques, including a new phase-sensitive 2D INADEQUATE experiment. The three-dimensional structure of patellin 2 was solved by x-ray crystallography and the two-dimensional structures of patellins 1 and 3-5 were assigned primarily by fast atom bombardment tandem mass spectrometry. These peptides are unique in having two modified threonine or serine dimethylallyl ethers and in the tendency for most members of the family to exist in two conformations, the ratio of which is a function of solvent