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The Development of new molecular scaffolds for nucleic acid condensation
McStay, Natasha
The discovery of new synthetic DNA recognition agents is an area of considerable research interest. The aim of this research was to develop novel trivalent scaffolds for the purpose of DNA condensation and examine through structure-activity relationships how these compounds bind and collapse the helical structure of DNA into particles suitable for passing through biological barriers. A major objective of this study was to investigate the use of synthetic tripodal C3- symmetric opioid scaffolds as efficient condensation agents of double stranded DNA (dsDNA). Morphine, codeine, heterocodeine, and oripavine C3-opioids were generated and showed comparable condensation capabilities. Condensation was achieved on both superhelical and linear dsDNA conformations and identified by agarose electrophoresis, viscosity, turbidity, and atomic force microscopy (AFM) measurements. Tripodal opioid aggregation was identified as pH dependent and strongly influenced by ionic strength with further evidence of cationic amine- phosphate backbone coordination. Since preliminary screening of the C3-oripavine opioid with selected mammalian cell lines indicated poor tolerance, the second aspect of this project focused on developing non-opioid DNA condensation agents. Tripodal imidazolium salts containing the same mesitylene core as the C3-opioids were therefore screened for potential activity. Results showed some evidence of DNA condensation but not at the same threshold as C3-opioids. Building on these results, a new library of terminal polyamine C3-scaffolds was prepared using the copper-catalysed azide-alkyne cycloaddition reaction. This new series, called “Tri-Click”, was developed as potential non-viral vectors for gene delivery with potentially lower cytotoxicity compared to tripodal opioids. The solubility of Tri-Click compounds was greatly improved compared to C3-opioids scaffolds but evidence of nucleic acid damage was also identified. This DNA damage mechanism was then probed using a variety of biophysical methods with specific trapping agents for reactive oxygen species (ROS) indicating single stranded DNA breaks mediated by copper-catalysed free radicals.
Keyword(s): Chemistry; Organic chemistry; Inorganic chemistry
Publication Date:
Type: Other
Peer-Reviewed: Unknown
Language(s): English
Contributor(s): Kellett, Andrew; Gathergood, Nicholas
Institution: Dublin City University
Citation(s): McStay, Natasha (2019) The Development of new molecular scaffolds for nucleic acid condensation. PhD thesis, Dublin City University.
Publisher(s): Dublin City University. School of Chemical Sciences
File Format(s): application/pdf
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First Indexed: 2019-04-04 06:05:20 Last Updated: 2019-04-04 06:05:20