The Characterization of cytotoxic metabolites from Fijian marine invertebrates

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Title The Characterization of cytotoxic metabolites from Fijian marine invertebrates
Publication Type dissertation
School or College College of Pharmacy
Department Medicinal Chemistry
Author Zabriskie, T. Mark
Date 1989-12
Description Marine 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.
Type Text
Publisher University of Utah
Subject Peptides, Cyclic; Porifera; Thiazoles; Urochordata
Subject MESH Antibiotics, Antifungal; Antineoplastic Agents; Insecticides; Invertebrates; Marine Biology
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "The Characterization of cytotoxic metabolites from Fijian marine invertebrates." Spencer S. Eccles Health Sciences Library. Print version of "The Characterization of cytotoxic metabolites from Fijian marine invertebrates." available at J. Willard Marriott Library Special Collection. QL3.5 1989 .Z32.
Rights Management © T. Mark Zabriskie.
Format application/pdf
Format Medium application/pdf
Format Extent 2,738,777 bytes
Identifier undthes,5352
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Funding/Fellowship American Foundation for Pharmaceutical Education and the University of Utah Research Committee fellowoships and the National Institutes of Health.
Master File Extent 2,738,869 bytes
ARK ark:/87278/s6sx6g01
Setname ir_etd
ID 190739
Reference URL https://collections.lib.utah.edu/ark:/87278/s6sx6g01
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