Bioassay-guided isolation of potential antineoplastic natural products from Southwestern plants
Author
Furbacher, Todd RaymondIssue Date
2001Advisor
Hoffmann, Joseph J.
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The University of Arizona.Rights
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.Abstract
This dissertation details the investigation of numerous plants for potential antineoplastic compounds. 144 plants (391 extracts) were prescreened with an assortment of assays. The pre-screens included an Agrobacterium tumefaciens/potato disk gall tumor inhibition assay, a Saccharomyces cerevisiae mutant topoisomerase assay, and an Escherichia coli plasmid scission assay. Bioassay-guided fractionation was conducted on three plants, Phoradendron juniperinum, Psorothamnus thompsoniae , and Acourtia thurberi, using a different assay for each. Phoradendron juniperinum (Viscaceae) was screened with a plasmid scission assay and the novel compound, 5-caffeoyl-epi-quinic acid (I) was isolated, the first chlorogenic acid to be reported for the genus. Chemical structure was established using NMR and MS data and published structural information. The EC₅₀ for 5-caffeoyl- epi-quinic acid-mediated plasmid DNA cleavage was 76 μM. Fractionation of Psorothamnus thompsoniae (Fabaceae) was directed using the potato disk assay. The active component was dalrubone (II). P. emoryi was fractionated to obtain dalrubone and to search for related compounds. 5-Methoxydalrubone (III) was isolated and tested with dalrubone in cell line assays. 5-Methoxydalrubone was active against MCF-7 (IC₅₀ = 28.2 μM), while dalrubone (IC₅₀ = 1.3 mM) was not. Neither compound significantly inhibited the growth of NCI-H460 or SF-268. Acourtia thurberi (Asteraceae) was active in the yeast mutant assay. Fractionation yielded the sesquiterpene, 14,15-diacetoxy-,8-hydroxy-,3-(3-methylbutanoyl)-14, 15-epoxy-isocedrene (IV). This compound was weakly active against the topoisomerase II sensitive yeast strain, RS321N, with an IC12 of 342 μg/mL. The isocedrene was active in the yeast assay but inactive against human topoisomerase IIalpha. Ten celastroloids (unsaturated, oxygenated D:A-friedo-nor-oleanane triterpenoids from Sri Lankan Celastraceae) and their derivatives, some of which were also weakly active against RS321N, were tested for activity against human topoisomerase IIalpha. Demethylzeylasterone (ex. Kokoona zeylanica) strongly inhibited topo IIalpha with an IC50 of 17.6 μM. All others, including the structurally similar zeylasterone, possessed no activity at 100 μM. Demethylzeylasterone was determined to be a "catalytic inhibitor," preventing DNA from binding to the enzyme while not interacting with the DNA itself. Demethylzeylasterone selectively inhibits the MCF-7 breast cancer cell line with an IC50 of 12.5 μM.Type
textDissertation-Reproduction (electronic)
Degree Name
Ph.D.Degree Level
doctoralDegree Program
Graduate CollegePharmaceutical Sciences