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dc.contributor.advisorSchÇÏrer, Orlando D.en_US
dc.contributor.authorGuainazzi, Angeloen_US
dc.contributor.otherDepartment of Molecular and Cellular Pharmacologyen_US
dc.date.accessioned2012-05-15T18:03:46Z
dc.date.available2012-05-15T18:03:46Z
dc.date.issued1-Aug-10en_US
dc.date.submittedAug-10en_US
dc.identifierGuainazzi_grad.sunysb_0771E_10155.pdfen_US
dc.identifier.urihttp://hdl.handle.net/1951/55445
dc.description.abstractMany of the drugs used in cancer chemotherapy target DNA to kill malignant cells. Some of them form DNA interstrand crosslinks (ICLs), which are extremely cytotoxic lesions that block essential metabolic process such as replication, transcription and recombination by forming covalent bonds between opposite strands of DNA. Despite the importance of chemotherapeutic agents that rely on ICLs for their efficacy, the mechanisms by which these lesions are repaired remains poorly understood. A major impediment in studying ICLs repair has been the limited availability of well-defined substrates. This dissertation describes the development of a new strategy for the synthesis of defined site-specific ICLs in high yields and purity. This strategy relies on the incorporation of ICL precursors bearing reactive aldehyde functionalities on complementary strands of DNA, followed by ICL formation via double reductive amination. We were able to synthesize different crosslinks that are isosteric to the therapeutic nitrogen mustard (NM) ICLs, introducing substitution of a few atoms to make them more stable and therefore more suitable for chemical, structural and biological studies.The synthetic substrates were validated through molecular dynamic studies, confirming that our mimic has all the essential structural features to its natural counterpart. Modeling data also demonstrate that both the natural and the synthetic ICL induce a bend in the DNA, which could play an important role in the way the lesion is repaired. Our synthetic approach furthermore allows for the synthesis of major groove ICLs with different degrees of distortion, providing unique and valuable tools for biochemical and cell biological studies of ICL repair.en_US
dc.description.sponsorshipStony Brook University Libraries. SBU Graduate School in Department of Molecular and Cellular Pharmacology. Lawrence Martin (Dean of Graduate School).en_US
dc.formatElectronic Resourceen_US
dc.language.isoen_USen_US
dc.publisherThe Graduate School, Stony Brook University: Stony Brook, NY.en_US
dc.subject.lcshHealth Sciences, Pharmacologyen_US
dc.subject.otherCancer chemotherapy, DNA repair, Interstrand Crosslinks, Nitrogen mustard, Reductive aminationen_US
dc.titleNitrogen Mustard Reloaded: Synthesis and Structural Studies of DNA Interstrand Crosslinksen_US
dc.typeDissertationen_US
dc.description.advisorAdvisor(s): Orlando D. Sch rer. Committee Member(s): Carlos De los Santos; Francis Johnson; Carlos Simmerling; Isaac Carrico.en_US
dc.mimetypeApplication/PDFen_US


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