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Two of the main treatments available to patients with cancer are radiation and chemotherapy which both rely on the ability to induce DNA damage. One reason cancer deaths perpetrate is due to cancer resistance towards current cancer therapies. The Base Excision Repair (BER) pathway is involved in therapeutic resistance by utilizing DNA glycosylases that recognize and remove the damaged DNA base to leave the aldehyde. Apyrimidinic/Apurinic (AP) enzyme 1, APE1, then recognizes the aldehyde to trigger DNA repair. Alkoxyamines function to competitively covalently bind the aldehyde generated from the AP site. Once the aldehyde is covalently bonded with the alkoxyamine, APE1 can no longer perform BER. Therefore, providing patients with alkoxyamine drug compounds, such as methoxyamine, CH3ONH2, current cancer therapies better survive cancer resistance. This is known as a combinatorial cancer therapy strategy. Currently, methoxyamine, TRC102, is being investigated in Phase I/II clinical trials for binding AP sites in DNA to inhibit the BER pathway. The focus of this research is to synthesize alkoxyamines and evaluate them as APE1 inhibitors. In particular, this work presented is focused on finding a synthetic route to generate alkoxyamines to potentiate current cancer therapies.

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Development of Anti-Cancer Small Molecules to Inhibit The Base Excision Repair (BER) Pathway By Binding Apyrimidinic/Apurinic (AP) Sites In DNA



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