Oligodeoxynucleotide Synthesis using Protecting Groups and a Linker Cleavable under Neutral Oxidative Conditions DNA analogs that contain latently reactive electrophilic functionalities can selectively form covalent bonds with target biomolecules such as DNA, mRNA, and protein through affinity induced reactions. As a result, they can be used as probes in research areas such as chemical biology, and have the potential to become a new class of therapeutic agents that have certain advantages over drugs based on small organic molecules and peptides. In addition, DNA derivatives that contain base-labile and electrophilic groups have been found in cells. They are results of important cellular processes and may play important cellular functions as well. Consequently, chemical synthesis of base-labile and electrophilic DNA analogs is important in health related research. Traditional DNA synthesis technologies use strongly basic and nucleophilic reagents, which are not compatible with base-labile and electrophilic groups, are not suitable for the purpose. A few reported methods intended to solve the problem have serious drawbacks including contamination of product by toxic transition metal, high cost of excessively used precious metal, damage of DNA by UV light, complicated post-DNA synthesis procedure, and narrow applications.
The specific aim of this project is to develop a universally useful technology for the synthesis of DNA analogs that contain a wide range of base-labile and electrophilic functionalities. To achieve the aim, protecting groups and linkers based on the 1,3-dithian-2-yl-methoxy organic function will be employed during DNA synthesis. With these groups and linkers, the technology does not require using any strong base, nucleophile, transition metal, and UV light in the entire process. The technology does not need any tedious and complicated post-DNA synthesis manipulations either. As a result, it will be practically useful for the synthesis of DNA analogs containing base-labile and electrophilic groups. Our long-term objective is to develop a new generation of antisense drugs based on latently reactive electrophilic DNA analogs. Successful completion of this project will build the foundation for us to achieve the objective. Importantly, the new technology will be widely used by other biomedical researchers all over the world as well. The PI believes that cultivating next generation biomedical researchers is equally important as meritorious research itself. This project will help the PI to train one postdoc, two PhD students and about six undergraduate researchers in the area of nucleic acid chemistry. They will learn techniques including organic synthesis, flash column chromatography, HPLC, NMR, MS, automated DNA synthesis, and gel electrophoresis. With this project, undergraduate students majoring in our pharmaceutical chemistry, biochemistry & molecular biology, cheminformatics, and chemistry programs will have a chance to participate in NIH- supported research. Their interests in pursuing a career in biomedical research will be enhanced. Our Chemistry Department has required infrastructure and instruments for research and education. This project will help us to maintain and improve our ability to make continued contributions.
Oligodeoxynucleotide Synthesis using Protecting Groups and a Linker Cleavable under Neutral Oxidative Conditions DNA analogs that contain latently reactive groups can selectively form covalent bonds with protein, mRNA and DNA through affinity induced reactions. They can be used as probes in chemical biology, and have the potential to become a new class of therapeutic agents. This project will develop a universal and practically useful technology for their chemical synthesis.
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