| dc.description.abstract | One of the most commonly used chemotherapeutic regimens is the adjuvant combination
therapy called Adriamycin/Cyclophosphamide (AC) Chemotherapy. These two drugs are understood to work separately to induce an additive therapeutic response. However, Adriamycin, also referred to as doxorubicin (DOX), is plagued with a highly cardiotoxic side effect. It is due to this side effect that there is a cumulative lifetime cap on the amount of DOX a patient can receive in his, her, or their lifetime. Past work in our lab has shown that cancer drugs like DOX are capable of binding to abasic/apyrimidinic (AP) sites in DNA, a lesion that forms both spontaneously and as a result of treatment with cyclophosphamide. Covalent adducts such as these have been cited as a source of DOX cytotoxicity in DOX-resistant cells, indicating that this may be a new mechanism of action for the drug. We have hypothesized that reversing the order of drug administration in AC Chemotherapy will result in a synergistic effect in the cell, where cyclophosphamide induces an AP site to which DOX binds covalently. However, these Schiff base conjugates hydrolyze at physiological pH. The aim of this dissertation is to synthesize a modification of anthraquinone compounds that will form conjugates with AP sites that will not hydrolyze at physiological pH. The modification synthesized in this dissertation is that of 2- aminoxyacetamides. These alkoxyamines form oxime conjugates with AP sites in DNA. To this end, we successfully have synthesized two anthraquinone analogs containing mono- and bis- substituted ethylenediamine arms, each with 2-aminoxyacetamides affixed to the primary amine(s). Authentic standards of our compounds bound to 2-deoxy-D-ribose were synthesized as a model for AP sites. Additionally, our compounds formed oxime conjugates with a 12-base pair DNA oligonucleotide with an induced AP site. Lastly, we have begun to elucidate the rate constants of our compounds’ reactions with this 12-base pair DNA oligonucleotide using the kinetic modeling software, COPASI. | |
