Design, Synthesis and Biological Evaluation of c-MYC G-Quadruplex Interactive Agents
AdvisorHurley, Laurence H.
Committee ChairHurley, Laurence H.
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PublisherThe University of Arizona.
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.
AbstractThe G-quadruplex secondary structure has evolved as a promising anti-tumor target in recent years. This distinctive structure has been proposed to form in the promoter regions of a variety of genes, including the c-MYC oncogene, which is over-expressed in 60% of cancers. The G-quadruplex structure in the c-MYC promoter acts as the repressor element, disruption of which leads to subsequent upregulation of the gene. Hence, stabilization of the G-quadruplex structure with small molecules has been an area of much interest. In this dissertation, the structural aspects of the c-MYC G-quadruplex, and development of unique ligands that stabilize this secondary DNA structure have been explored. The G-quadruplex structure adopts an intramolecular parallel-stranded conformation in solution, and various ligands have been shown to induce structural changes. Cationic porphyrins are such a class of compounds that selectively bind to and stabilize the c-MYC G-quadruplex and in some cases also induce a structural change. The extensively studied cationic porphyrin, TMPyP4, stabilizes the c-MYC G-quadruplex and represses the gene transcription. This detail has been the basis of the research presented herein. Structure-based drug design has been used to develop other novel ligands having bisintercatating properties for enhanced stabilization of the G-quadruplex. A hybrid molecule, having both intercalation and alkylation properties, has also been investigated that has shown to lower the gene expression. Thus, a prototype of ligands are presented that can serve as the base for development of compounds with promising therapeutic properties.