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Controlled Synthesis of Nucleic Acid-Polymer Hybrids via Atom Transfer Radical Polymerization
In this thesis, novel strategies for the controlled synthesis of nucleic acid-polymer hybrids (NAPH) are discussed. Chapter 1 introduces a comprehensive summary of previously reported synthetic pathways and applications of NAPH, providing an introduction to the state-of-the-art research on NAPH and the fundamentals of controlled radical polymerization methods. Chapters 2–7 cover the research projects in which I participated as the first author during my Ph.D. studies.
In Chapters 2 and 3, site-controlled incorporation of ATRP initiator(s) in synthetic oligonucleotides during the solid-phase DNA/RNA synthesis was demonstrated. This innovative incorporation strategy was facilitated by the development of a new reagent, serinol-based α?bromoisobutyryl (SBiB) phosphoramidite, which is equipped with an ATRP initiator. During the solid-phase oligonucleotide synthesis, SBiB can be incorporated anywhere in DNA or RNA, allowing precise growth of the synthetic polymer from the ATRP initiator in the SBiB residue (Chapter 2). This method can also be extended for the synthesis of RNA amphiphiles through growing hydrophobic polymer from RNA in DMSO (Chapter 3).
Chapters 4 and 5 describe the utilization of acyl imidazole chemistry strategies for the incorporation of the ATRP initiator (Chapter 4) or a polymerizable vinyl group (Chapter 5) within RNA. These methods offer a universal and versatile route for the synthesis of RNA bottlebrush polymer (Chapter 4) or degradable biomass RNA hydrogels (Chapter 5) in a post-synthetic manner (i.e., after solid-phase synthesis or transcription) without the assistance from an oligonucleotide synthesizer machine
In Chapter 6, I demonstrated that nucleic acids, in combination with appropriate nucleic acid-binding dyes (NuABDs), can be utilized as a photocatalyst for photoATRP. NuABDs are a unique class of fluorescent probes that become fluorescent exclusively after binding to specific nucleic acids. Chapter 6 shows that multi-dimensional nucleic acid scaffolds (e.g., dsDNA, G-quadruplex, micron-sized DNA particles) can successfully mediate the radical polymerization process in conjunction with the appropriate NuABD.
Chapter 7 describes a photoinduced click reaction system (CuAAC, copper-catalyzed azide–alkyne cycloaddition) using highly water-soluble sodium pyruvate (SP) as a non-toxic photoreducing agent. In the proposed SP-CuAAC, SP is an essential component that enables the reduction of the Cu(II) precatalyst under UV light irradiation and scavenges reactive oxygen species. This system has been proven to be an efficient method for modifying DNA at low volumes in a temporally controlled manner under bio-friendly conditions in an ambient atmosphere. I also demonstrated that thisprotocol caused negligible effects on cytotoxicity and cell proliferation.
Finally, Chapter 8 provides a summary of the studies presented in this dissertation on the controlled synthesis of NAPH. In addition, future perspectives and new directions for advancing the field of NAPH are provided
History
Date
2024-01-31Degree Type
- Dissertation
Department
- Chemistry
Degree Name
- Doctor of Philosophy (PhD)