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dc.contributor.advisorTrawick, Mary Lynn.
dc.contributor.authorMugabe, Benon E.
dc.contributor.otherBaylor University. Dept. of Chemistry and Biochemistry.
dc.date.accessioned2006-05-29T01:59:46Z
dc.date.available2006-05-29T01:59:46Z
dc.date.copyright2005
dc.date.issued2006-05-29T01:59:46Z
dc.identifier.urihttp://hdl.handle.net/2104/3019
dc.descriptionIncludes bibliographical references (p. 259-273).en
dc.description.abstractInhibition of tubulin polymerization has been identified as a significant characteristic of potential anticancer agents. Tubulin is a heterodimeric protein of a and b polypepetide chains, each with a molecular weight of 50kDa and is the biochemical target for several clinically used anticancer drugs. Tubulin was purified from calf brain by a method that uses a series of selective polymerizations induced by a temperature jump in the presence of GTP followed by cold depolymerization. Protein purity was determined by SDS-PAGE and the ability of tubulin to polymerize into microtubules. As part of a program to identify vascular disrupting agents (VDAs), we have determined the effect of more than 78 combretastatin A-4 and A-1 analogs on tubulin polymerization. Combretastatin analogs with substitutions in both the trimethoxyphenyl and phenolic rings were analyzed. These included bromo, chloro, fluoro, mono and di-nitro, di-amino and di-amino hydrochloride, serinamides, serinamide hydrochloride salts of CA-4 and CA-1 derivatives many of which showed good antitubulin activities (IC50 = 1.1 – 3.0 µM) which were comparable to those of CA-1 and CA-4. Generally, water soluble combretastatin phosphate salts analyzed did not show significant inhibitory activity on tubulin polymerization. Our research also explored the application of isothermal titration calorimetry in determining the thermodynamic parameters of binding of CA-1, CA-4 and some of their derivatives. Microcalorimetric studies of the interactions between tubulin and combretastatin analogs were designed to directly determine the enthalpy, binding affinity and the number of binding sites involved upon interaction. We have defined the various thermodynamic signatures that characterize interaction of these compounds with tubulin. All tubulin-combretastatin analog interactions were exothermic and showed favorable free energies and binding affinity constants (0.1 – 9.8 x 105 M-1). The binding affinity constants, stoichiometry, and the thermodynamic signatures suggested hydrogen bonding and hydrophobic contacts for the stronger binding interactions between CA-1 and its analogs which were both enthalpy and entropy driven whereas 2,3 di-amino CA-1 and others showed low binding constants, with evidence of conformational changes upon binding.en
dc.description.statementofresponsibilityby Benon E. Mugabe.en
dc.format.extentxxviii, 273 p. : ill.en
dc.format.extent12957337 bytes
dc.format.mimetypeapplication/pdf
dc.language.isoen_USen
dc.rightsBaylor University theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. Contact librarywebmaster@baylor.edu for inquiries about permission.en
dc.subjectTubulins.en
dc.subjectPolymerization.en
dc.subjectLigand binding (Biochemistry).en
dc.subjectAffinity electrophoresis.en
dc.titleStructure-activity relationships and thermodynamics of combretastatin A-4 and A-1 derivatives as potential inhibitors of tubulin polymerization.en
dc.typeThesisen
dc.description.degreePh.D.en
dc.rights.accessrightsWorldwide access.en
dc.rights.accessrightsAccess changed 5/24/11.
dc.contributor.departmentChemistry and Biochemistry.en


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