Bioassay-guided isolation of potential antineoplastic natural products from Southwestern plants

Persistent Link:
http://hdl.handle.net/10150/279927
Title:
Bioassay-guided isolation of potential antineoplastic natural products from Southwestern plants
Author:
Furbacher, Todd Raymond
Issue Date:
2001
Publisher:
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:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Pharmacology.; Chemistry, Pharmaceutical.; Health Sciences, Oncology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmaceutical Sciences
Degree Grantor:
University of Arizona
Advisor:
Hoffmann, Joseph J.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleBioassay-guided isolation of potential antineoplastic natural products from Southwestern plantsen_US
dc.creatorFurbacher, Todd Raymonden_US
dc.contributor.authorFurbacher, Todd Raymonden_US
dc.date.issued2001en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © 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.en_US
dc.description.abstractThis 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.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Pharmacology.en_US
dc.subjectChemistry, Pharmaceutical.en_US
dc.subjectHealth Sciences, Oncology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmaceutical Sciencesen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorHoffmann, Joseph J.en_US
dc.identifier.proquest3040145en_US
dc.identifier.bibrecord.b42562569en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.