The purpose of this project is to determine the sequence specificity of novel propargylic sulfone compounds for DNA. Previous studies have shown that propargylic sulfones, a new class of DNA-cleavage agents, possess both cytotoxicity to cultured cancer cells and cleavage potency to plasmid DNA. Thus, propargylic sulfones are potential anti-tumor drugs. However, little is known about the sequence specificity and the interaction with DNA, at the molecular level, of these novel propargylic sulfones. This lack of knowledge is a barrier to increasing the efficacy of the compounds. Footprinting, circular dichroism (CD) and nuclear magnetic resonance (NMR) studies are used as tools to provide information on the sequence specificity of two propargylic sulfones and the structural changes that on...[ Read more ]

The purpose of this project is to determine the sequence specificity of novel propargylic sulfone compounds for DNA. Previous studies have shown that propargylic sulfones, a new class of DNA-cleavage agents, possess both cytotoxicity to cultured cancer cells and cleavage potency to plasmid DNA. Thus, propargylic sulfones are potential anti-tumor drugs. However, little is known about the sequence specificity and the interaction with DNA, at the molecular level, of these novel propargylic sulfones. This lack of knowledge is a barrier to increasing the efficacy of the compounds. Footprinting, circular dichroism (CD) and nuclear magnetic resonance (NMR) studies are used as tools to provide information on the sequence specificity of two propargylic sulfones and the structural changes that one of them induces in DNA upon binding. The results of these studies will assist in the rational design of more effective drugs from these compounds.

This thesis contains an overview of drug-DNA interactions with emphasis on current research on the novel DNA-cleaving molecules: propargylic sulfones. Original results on the site and sequence specificity of two propargylic sulfones molecules, which were shown to be able to cleave DNA, were obtained by footprinting experiments. Preliminary structural studies of the DNA-drug complex formed by one of these compounds were performed using two spectroscopic methods, circular dichroism (CD) and nuclear magnetic resonance (NMR).

A summary of the major findings of this project are also presented.