Design, synthesis and biological evaluation of c-MYC G-quadruplex interactive agents

The 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.