dc.contributor.advisor | Georg, Gunda I. | |
dc.contributor.author | Beckman, Karen | |
dc.date.accessioned | 2009-02-02T05:49:17Z | |
dc.date.available | 2009-02-02T05:49:17Z | |
dc.date.issued | 2008-09-04 | |
dc.date.submitted | 2008 | |
dc.identifier.other | http://dissertations2.umi.com/ku:2726 | |
dc.identifier.uri | http://hdl.handle.net/1808/4334 | |
dc.description.abstract | This thesis describes the rationale, design, and syntheses of derivatives of isatin (1-H-indole-2,3-dione). Isatin was identified, during a high throughput screen of 10,000 compounds, as a potential scaffold for microtubule-destabilizing agents. Additional screening of purchased isatin derivatives gave rise to four substitution patterns of interest, 7-arylisatins, 5-methyl-N¬-alkyl/aryl isatins, 5-chloro-N-alkyl/aryl isatins and 5,7-dichloro-N-alkylated isatins. Series of compounds with the substitutions of interest were synthesized to further probe the structure-activity relationship (SAR) of isatin. The SAR study showed that substitutions in the 5- and 7- positions of the aromatic ring combined with N-substitutions increased the disruption of microtubule assembly. The 7-phenylisatin and N-arylisatin derivatives were inactive in the biological assay. Several of the 5-chloro-N-alkylisatins and the 5,7-dichloro-N-alkylisatins were cytotoxic in both MCF-7 and NCI/ADR-RES cell lines. 5,7-Dichloro-N-(4-bromobenzyl)isatin was the most active compound against MCF-7 cells, IC50 = 2.1 µM. To date the most cytotoxic compound tested is 5-methyl-N-(1-propyl)isatin, with an IC50 value of 52 nM (microtubule assembly IC50 = 2.6 µM) in the drug resistant cancer cell line NCI/ADR-RES. | |
dc.format.extent | 93 pages | |
dc.language.iso | EN | |
dc.publisher | University of Kansas | |
dc.rights | This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author. | |
dc.subject | Organic chemistry | |
dc.subject | Chemistry | |
dc.subject | Biochemistry | |
dc.subject | Medicinal chemistry | |
dc.title | Isatin Derivatives as Inhibitors of Microtubule Assembly | |
dc.type | Thesis | |
dc.contributor.cmtemember | Himes, Richard | |
dc.contributor.cmtemember | Blagg, Brian S. J. | |
dc.thesis.degreeDiscipline | Medicinal Chemistry | |
dc.thesis.degreeLevel | M.S. | |
kusw.oastatus | na | |
kusw.oapolicy | This item does not meet KU Open Access policy criteria. | |
kusw.bibid | 6857369 | |
dc.rights.accessrights | openAccess | |