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Synthesis of Structurally Diverse Major Groove DNA Interstrand Crosslinks

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dc.contributor.advisor Scharer, Orlando D en_US
dc.contributor.author Mukherjee, Shivam en_US
dc.contributor.other Department of Chemistry en_US
dc.date.accessioned 2017-09-20T16:52:03Z
dc.date.available 2017-09-20T16:52:03Z
dc.date.issued 2014-12-01 en_US
dc.identifier.uri http://hdl.handle.net/11401/77135 en_US
dc.description 158 pgs en_US
dc.description.abstract 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. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Chemistry en_US
dc.title Synthesis of Structurally Diverse Major Groove DNA Interstrand Crosslinks en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Raleigh, Daniel en_US
dc.contributor.committeemember Simmerling, Carlos en_US
dc.contributor.committeemember Santos, Carlos De los en_US

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