Synthesis and Characterization of Fluorescent and Potentially Bioactive DNA-Targeting Platinum Complexes

Abstract

Guanine quadruplexes (G4s) are non-canonical folded motifs of DNA and RNA which have received growing attention in the past 30 years as they appear to participate in the regulation of cell senescence, the production of proteins, and RNA functions. Specifically, guanine quadruplexes are often more frequently encountered in the gene promoter regions of many human cancer oncogenes. The stabilization of a guanine quadruplex using a small molecular ligand has shown to inhibit transcription, affecting the cancerous activity of the cell. Chemists can play a significant role through the tuning of ligands. The chemical nature of the binding platform of small molecules can be adjusted in order to improve selectivity towards guanine quadruplex over duplex DNA, which recently has been very effectively achieved in our group, in the development of a platinum-based complex which is highly selective towards guanine quadruplexes. In this work, the efforts towards synthesizing a luminescent BODIPY ligand to be used for cellular visualization, as well as a potentially bioactive 15-carbon urea fatty acid moiety, which has previously been shown to target the mitochondria and induce apoptosis are described. The end-goal of this research is to increase the selectivity for G4 motifs, to improve the effectiveness of the platinum complex towards cancerous cells, and importantly to eventually translate this technology in vivo. In order to effectively study the platinum complexes in cells, an imaging method is required to visualize cell entry and locate these agents. To this end, BODIPY dyes have been synthesized and attached to the G4-targeting Pt complex, and the efficient syntheses of these conjugates are detailed in Chapter 2. Their luminescent properties have been explored in the absence and presence of G4s, and their use as a reference dye for biophysical assays is discussed. The focus of the second ligand is the synthesis of a 15-carbon potentially bioactive urea fatty acid, as well as a 10-carbon test urea fatty acid molecule, and their incorporation into the platinum complex. Their synthesis are described in Chapter 3.