The Clean Cut: Design, Synthesis, Assay Optimization, and Biological Evaluation of Compounds That Can Produce Double Strand Breaks in Deoxyribonucleic Acid

Abstract

Delivery of drug molecules to desired targets has been of utmost importance to maximize efficacy and minimize off-target toxicity. Currently, cancer patients receive chemotherapy which affects malicious and healthy cells in the body, leading to universal damage throughout the body. Antibody drug-conjugates (ADCs), which are composed of an antibody linked to a drug molecule with a chemical chain, have potential to deliver cytotoxic drugs to cancer cells that express unique receptors recognized by the antibody. This targeted drug therapy can minimize the undesired and harmful side effects of cytotoxic chemotherapy currently available. In the early stages of this project, juglone-derivatives were synthesized as potential double-strand break inducing agents and tested using bacterial DNA in a DNA Cleaving Assay. This process entailed optimizing visualization of DNA cleavage using gel electrophoresis. Though the juglone-derivatives did not cleave effectively, nitracrine-derivatives were found to create single-stranded breaks, showing potential for the use of nitracrine compounds as DNA cleaving agents on ADCs for cancer treatment.