Structure Function Analysis of Thymidine Analogs: Correlating DNA Incorporation with Anti-Tumor Efficacy

Abstract

This thesis, "Structure Function Analysis of Thymidine Analogs: Correlating DNA Incorporation with Anti-Tumor Efficacy," explores the relationship between structural modifications of thymidine analogs and their impact on anti-tumor activity, specifically focusing on lung and colorectal cancers. Under the guidance of Professor Joshua Rabinowitz and Dr. Jacob Boyer, this research assesses how alterations at the 5-position and the 2’-position influence the efficacy of thymidine analogs in inhibiting cancer cell proliferation. The study systematically evaluates various commercially available and novel thymidine analogs for their growth inhibitory properties, capabilities for DNA incorporation, and their potential to induce DNA damage. The findings reveal that structural modifications significantly affect the compounds' ability to interfere with thymidylate synthase, a key enzyme in DNA synthesis, and DNA damage. The interplay between the chemical structure of thymidine analogs and their biological functions is complex, while the work elucidates the mechanism of clinically relevant compounds, classifying compound via a matrix of thymidylate synthase inhibition vs. DNA incorporation. While some analogs show promise due to their enhanced interactions with biological targets, others require further refinement and exploration of alternative pathways such as pro-tides for effective cancer treatment. Future research must delve deeper into the molecular mechanisms of action of these analogs as continued exploration of thymidine analogs holds the key to unlocking advances in lung and colorectal cancer treatment.