A great number of pharmaceutical drugs target nucleic acids. However, drug-DNA interactions can be region non-specific and lead to undesired side effects. Understanding the mechanisms that regulate drug-DNA binding can help in the design of potent and selective therapeutic agents with fewer deleterious side effects. The present investigation explores the metal-mediated DNA binding of a group of 2-(2-hydroxyphenyl)benzoxazole (HPB) ligands and the aggregation dependant G-quadruplex selectivity of a series of perylene tetracarboxylic acid diimides (PTCDI) compounds. HPB ligands are simplified analogs of the bis-benzoxazole natural product UK-1. This compound is able to inhibit cell growth of various tumor cell lines, bind divalent cations, and interact with DNA in a metal dependant fashion. The HPB moiety present in UK-1 was identified as relevant for its metal ion binding and biological properties. For this work, novel HPB ligands were synthesized with different substitutions at the C4 or C7 position. Their ability to bind metal ions and DNA was evaluated and their cytotoxicity was assessed in multiple cancer cell lines. The ligands bound to Cu²⁺ with the highest affinity among metals studied. Consequently, Cu²⁺ promoted the most dramatic increase in DNA binding and affected the ligand's cellular cytotoxicity. The second project focused on targeting four-stranded structures called G-quadruplexes, which can form in G-rich nucleic acid sequences. Compounds that stabilize these structures may inhibit nucleic acid-processing enzymes such as telomerase and potentially act as anti-cancer agents. PIPER is a PTCDI that is particularly selective for G-quadruplex DNA versus duplex DNA under conditions in which it forms aggregates. This work investigated ligand aggregation in a series of PIPER analogs with different structural features under high and low salt buffers, changes in pH, metal binding and temperature changes. A negatively charged analog was determined to form metal-mediated aggregates while novel thermophilic mediated aggregation was discovered for an analog with methoxyethoxymethyl groups. The ability of these ligands to bind different DNA structures was evaluated under aggregating and non-aggregating conditions. This study supports the idea that ligand aggregation increases their quadruplex selectivity and decreases double-stranded DNA binding.
| Identifer | oai:union.ndltd.org:UTEXAS/oai:repositories.lib.utexas.edu:2152/3634 |
| Date | 29 August 2008 |
| Creators | McKee, Mireya Loreley, 1978- |
| Contributors | Kerwin, Sean M. |
| Source Sets | University of Texas |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | electronic |
| Rights | Copyright © is held by the author. Presentation of this material on the Libraries' web site by University Libraries, The University of Texas at Austin was made possible under a limited license grant from the author who has retained all copyrights in the works. |
Page generated in 0.0084 seconds