Metallodrugs as inducers and inhibitors of chemical nuclease activity
Prisecaru, Andreea (2015) Metallodrugs as inducers and inhibitors of chemical nuclease activity. PhD thesis, Dublin City University.
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Manipulation of DNA is both an intrinsic and essential component of molecular biology and biotechnology. Reagents capable of cutting DNA are applied within these fields as probes for DNA structure and function, with the ultimate aim being the design of target-specific—customised endonucleases—capable of modifying genomic DNA. Thus, DNA cleaving reagents are essential tools for both sequence analysis and genome engineering. Furthermore, the discovery of new molecular mechanisms by which small molecules modify DNA structure, reactivity, and biological repair contributes significantly to potential drug development.
The chemical nuclease of [Cu(Phen)2]2+ (where Phen = 1,10-phenanthroline), is a well studied reagent which randomly cleaves nucleic acids in the presence of molecular oxygen (or hydrogen peroxide) upon reduction to Cu+. In addition, compounds based on this chemotype have found application in the biological field as antimicrobial and anticancer agents, DNA intercalators, and as nucleoside constituents for incorporation into the DNA backbone. [Cu(Phen)2]+ oxidises duplex DNA without specificity, predominately at the minor groove with C-H bonds at C1′, C4′, and C5′ being the main targets of hydrogen atom abstraction.
The aim of this research was to extend structure-activity relationships of Cu2+-Phen complexes containing sterically functionalized pendant carboxylates and to investigate how synthetic extension of the ligated phenazine ligand within this complex model influences DNA recognition and oxidative degradation. These compounds have shown an enhanced DNA recognition relative to the well-studied chemical nuclease, [Cu(Phen)2]+. Furthermore, the effects of nuclearity on DNA oxidation were elucidated using the [Cu(-terephthalate)(Phen)4]2+ cation with results showing potent DNA oxidation in the absence of exogenous reductant. Many compounds developed in this work constitute a series of novel anticancer leads capable of intracellular DNA oxidation leading to genomic double strand breaks. In addition to the application of developmental metallodrugs as inducers of chemical nuclease activity, the effects of cytotoxic trinuclear platinum(II) complexes as high-affinity DNA binders that inhibit—or block—endonuclease enzyme recognition and excision are reported through a wide variety of biophysical and molecular biological methods.
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