Synthesis of Structurally Diverse Major Groove DNA Interstrand Crosslinks.

摘要

DNA Interstrand Cross-links (ICLs) are extremely cytotoxic lesions caused by a variety of endogenous and exogenous agents. ICLs prevent the separation of two DNA strands and hence block essential cellular functions such as DNA transcription and replication. ICL causing agents are widely used in cancer chemotherapy and the removal of ICLs is associated with the resistance to anticancer agents. Despite the clinical importance of ICLs, the details of the pathways by which these lesions are repaired remain poorly understood.;This dissertation focuses on the synthesis of structurally diverse major groove DNA ICLs that induce different degrees of distortion into the DNA. We synthesized a three-carbon alkyl-aldehyde precursor and used it along with one and two carbon precursors to form a range of ICLs with different amines using the strategy of post-synthetic reductive amination. The newly formed ICLs induce little, moderate or no distortion into the DNA and provide insights into the structure and reactivity parameters of ICL formation by double reductive amination. These ICLs will be valuable substrates for exploring structure-activity relationships in ICL repair.;Additionally, we synthesized a 7-deazaguanosine moiety having an alkyl-amino linker and coupled it to an oligonucleotide having an aldehyde precursor to form an ICL connected by a single base. We also generated ICLs that were used to in collaborative efforts to study the role of structure-specific endnonucleases in ICL repair.