Abstracts Category : Other

Copper(II) Phenanthrene and Naphthalene Oxidative Chemical Nucleases

by Zara Molphy

Since the structural elucidation of duplex DNA, the construction of small molecules that recognise and react at specific sites to modify DNA structure, reactivity and biological repair mechanisms has been an area of considerable research interest. The discovery of the first synthetic chemical nuclease [Cu(phen) 2 ] 2+ (where phen = 1,10-phenanthroline) has sparked intensive effort toward the development of new artificial metallonucleases. [Cu(phen) 2 ] 2+ binds both nucleic acids and proteins without specificity inducing general toxicity, and is thus considered a promiscuous agent. Accordingly, manipulation of this chemotype represents an interesting developmental challenge. The first part of this work thus reports a range of novel Cu 2+ chemical nucleases of [Cu(phen),(N,N)] 2+ carrying designer phenazine type-intercalators (where N,N = DPQ, DPPZ and DPPN) were developed to identify how systematic extension of the ligated phenanthrene group influences nucleotide binding affinity, base selectivity, oxidative chemical nuclease activity, and cytotoxicity within human cancer cells. Agents within this series showed potent intercalative selectivity with high-affinity binding constants among the highest reported to-date.Since the introduction of two metal centres into complex scaffolds has uncovered nucleic acid binding interactions not possible through the use of simple univalent compounds with recent examples including the cytotoxic self-activating DNA oxidant [Cu 2 (- terephthalate),(phen) 4 ] 2+ the development of new polynuclear complexes is an area of considerable research interest. With this in mind, the second part of this thesis reports a new di-Cu 2+ complex [Cu 2 (tetra-(2-pyridyl)-naphthalene)Cl 4 ] (Cu 2 TPNap) that was rationally designed based on i.) the utility of a tetra-2-pyridine ligand scaffold for efficient nucleic acid catalytic cleavage within previously reported di-Zn 2+ systems, and ii.) the introduction of an aromatic DNA binding moiety that can potentially enhance both nucleic acid targeting and binding affinity. Using a range of molecular biological and spectroscopic techniques, Cu 2 TPNap was identified to bind DNA non-intercalatively at the major groove inducing guanine-cytosine specific deformation and condensation. The complex oxidatively damages DNA through a superoxide-mediated process leading to strand breakages in the absence of co-activating exogenous species.The final part of this thesis reports the discovery of a new class of DNA condensation agent featuring a C 3 -symmetric opioid scaffold. These agents, which may have potential gene transfection properties, were identified to collapse the tertiary structure of duplex DNA polymers through phosphate ionic interactions at a protonated piperidine site on the opioid molecule. Using a series of molecular biological and biophysical assays, the binding interactions and structural requirements for this new class of agent were uncovered and are described herein.Advisors/Committee Members: Kellett, Andrew, IRCSET.