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Design, Synthesis and Biological Evaluation of Ring-constrained and Biphenyl Derivatives as Hsp90 C-terminal Inhibitors
dc.contributor.advisor | Blagg, Brian S. J. | |
dc.contributor.author | Garg, Gaurav | |
dc.date.accessioned | 2016-10-11T16:00:32Z | |
dc.date.available | 2016-10-11T16:00:32Z | |
dc.date.issued | 2014-05-31 | |
dc.date.submitted | 2014 | |
dc.identifier.other | http://dissertations.umi.com/ku:13323 | |
dc.identifier.uri | http://hdl.handle.net/1808/21633 | |
dc.description.abstract | Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that plays a pivotal role in protein homeostasis in responses to cellular stress. Hsp90 regulates the conformational maturation, activation, and integrity of a wide array of client proteins, including oncogenic proteins (Her2, Raf1, Akt, CDK4 etc.) associated with all six hallmarks of cancer. Consequently, Hsp90 inhibition offers a unique opportunity for the simultaneous degradation of multiple anti-cancer targets and hence, for the development of cancer chemotherapeutics. Hsp90 exists as a homodimer with each monomer consisting of a druggable domain; the N-terminal domain, the middle domain, and the C-terminus. The majority of research has focused on development of Hsp90 N-terminal inhibitors. In fact, all Hsp90 inhibitors in clinical trials belong to this class. One of the major drawbacks associated with N-terminal inhibitors is the concomitant induction of the pro-survival response, which results in an upregulation of Hsp's and affects the dosing schedule. As a result, alternative strategies are sought for the development of future Hsp90 inhibitors. Over the last decade, Hsp90 C-terminal inhibitors have emerged an attractive alternative for Hsp90 modulation. These inhibitors exhibit similar inhibitory activity to N-terminal inhibitors, but do not induce the pro-survival response and could potentially circumvent the clinical limitations imposed on N-terminal Inhibitors. Presented herein are the design, synthesis and biological evaluation of ring-constrained novobiocin analogues that provide new insights into the Hsp90 C-terminal binding pocket and SAR's that can be used for future analog development. In addition, identification of a novel class of Hsp90 inhibitors is discussed. These new agents provide a platform upon which future Hsp90 inhibitors can be built upon. | |
dc.format.extent | 165 pages | |
dc.language.iso | en | |
dc.publisher | University of Kansas | |
dc.rights | Copyright held by the author. | |
dc.subject | Pharmaceutical sciences | |
dc.subject | Organic chemistry | |
dc.title | Design, Synthesis and Biological Evaluation of Ring-constrained and Biphenyl Derivatives as Hsp90 C-terminal Inhibitors | |
dc.type | Thesis | |
dc.contributor.cmtemember | Dutta, Apurba | |
dc.contributor.cmtemember | Hanson, Paul | |
dc.thesis.degreeDiscipline | Medicinal Chemistry | |
dc.thesis.degreeLevel | M.S. | |
dc.provenance | 04/04/2017: The ETD release form is attached to this record as a license file. | |
kusw.bibid | 8086541 | |
dc.rights.accessrights | openAccess |
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Medicinal Chemistry Dissertations and Theses [80]
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Theses [4088]