Type
Text
Type
Dissertation
Advisor
Carlos De los Santos | SchÇÏrer, Orlando D. | Francis Johnson | Carlos Simmerling | Isaac Carrico.
Date
2010-08-01
Keywords
Cancer chemotherapy, DNA repair, Interstrand Crosslinks, Nitrogen mustard, Reductive amination | Health Sciences, Pharmacology
Department
Department of Molecular and Cellular Pharmacology
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/70872
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Many 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.
Recommended Citation
Guainazzi, Angelo, "Nitrogen Mustard Reloaded: Synthesis and Structural Studies of DNA Interstrand Crosslinks" (2010). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 81.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/81