Studies of a G-quadruplex-specific cleaving reagent, expansion of long repetitive DNA sequences, and a cytosine-specific alkylating aza-enediyne

This dissertation focuses on the structural and dynamical diversity of DNA. As a biological macromolecule, DNA possesses a wide variety of secondary and super structures that lead to highly specific interactions with small molecules, cellular proteins, and other macromolecules. The composition and structure of DNA constantly changes to serve the normal physiology of the cell and, consequently, the whole body. Many diseases arise from the malfunction(s) or disruption(s) of these normal cellular activities. From a medical standpoint, the ability to recognize a particular structure offers potential cures for disease. The majority of the studies presented in this dissertation focus on the telomere---a segment of DNA located at the end of the chromosome---because of its relationship with the immortal character of cancer cells. The well defined, ordered sequence of the telomere allows it to form a particularly stable structure called "G-quadruplex", which is believed to play important roles in both normal and abnormal cellular activities. Chapter 1 provides background knowledge of the topics studied in this dissertation. Chapter 2 presents the design and synthesis of G-quadruplex specific cleaving reagent. Chapter 3 presents solution structures and stability of unimolecular quadruplex formed from two different telomeric sequences and their possible roles in biology. Chapter 4 explores the possible dynamic instability of telomeric sequences that arises from the repetitive nature of these sequences, the studies of in vitro expansion by DNA polymerase. Finally, Chapter 5, which relates not at all to the telomere or telomeric sequence, nevertheless demonstrates the diversity of DNA on the basis of its primary structure. Specifically, Chapter 5 examines the interaction between DNA and a synthetic heterocyclic aza-enediyne that induces a novel cytosine-specific alkylation.