Exploring Silver-Pyrimidine Chemistry and the Controlled Assembly of M-DNA Systems

Abstract

The body of work discussed within this thesis focuses on silver-pyrimidine chemistry traditionally found between a mismatched cytosine-cytosine (C-C) DNA base-pair. Three examples of [AgI -bis-(N3 -cytosine)]+ were prepared and structurally characterised by single crystal X-ray diffraction: cisoidal-[AgI -(N 3 -cytosine)2][NO3] (Cbent), transoidal-[AgI -(N 3 - cytosine)2][NO3]·H2O (Tbent) and transoidal-[AgI -(N 3 -cytosine)2][PF6]·2H2O (Tlinear). All three compounds displayed the typical N3 -AgI -N3 coordination motif with variable geometries including, cisoidal/transoidal (C/T) and bent/linear base arrangements. Collectively, they represent three of five possible combination of these parameters. Density-Functional theory calculations showed the global minimum conformation to be the bent-transoidal arrangement; the entire series being Tbent > Tlinear > Clinear > Cbent. [AgI -bis-(N 3 -cytidine)][NO3] was prepared and structurally characterised by single crystal X-ray diffraction techniques and revealed to show the expected linear N 3 -AgI -N 3 coordination. The resulting bis-nucleoside (ribose form) complexes spontaneously stacked inline to produce a helical arrangement (right-handed) analogous to DNA (approximately 10-bp per rotation). In solution, a significant change in the circular dichroism profile was observed compared to cytidine(aq) and was associated with the formation of helical structure. The helix is stabilised by hydrogen bonding between adjacent exocyclic N 4 ···O 2 groups of the ligands, argentophilic and hydrophilic interactions. The silver ions positioned down the central core are sufficiently close, with Ag···Ag distances of approximately 3.0 Å for argentophilic interactions. Despite having Ag···Ag distances <5% of the metallic radii, the material displayed electrically insulating properties, likely due to a large bandgap (2.5 eV). Furthermore, when prepared in an alcoholic solvent (MeOH and EtOH) the corresponding silver complex produced a sample-spanning homogenous gel. A rheological study showed an entangled network with thixotropic (self healing) properties. [AgI -bis-(N 3 -2’-deoxycytidine)][NO3] was prepared and structurally characterised by single crystal X-ray diffraction to show a similar helical arrangement to its ribose counterpart. However, the deoxy analogue possessed a left-handed (LH) rotation to the helix. Interestingly, the CD changes previously associated with a helical structure were similar for both the ribose (RH) and deoxy (LH) compounds. Atomic force microscopy imaging of the complex drop-cast from an aqueous solution on to a silicon wafer showed coiled fibres 10 nm in height. Individual coils could be followed into larger aligned assemblies or bundles before merging with the 3 crystal lattice. These images hold an insight into the mechanisms of crystal growth for polymeric systems. Two solvates of the nucleotide complex [AgI -(N 3 ,O 2 -cytidine-5’-monophosphate)] (Cmp) were prepared and structurally characterised by single crystal X-ray diffraction; cis-[AgI -(N 3 ,O2 - Cmp)][NO3]·H2O and cis-[AgI -(N 3 ,O2 -Cmp)][NO3]·MeOH. A one-to-one stoichiometry extends the repertoire of metal coordination sites of cytosine to include the exocyclic O2 acceptor group. This mode of coordination (N3 -AgI -O2 ) leads to a polymeric array where the AgI ions “zigzag” down the crystal lattice axis. This configuration means the Ag···Ag distances are short, at 2.9 Å. Furthermore, both compounds exist as 3D coordination polymers owing to a third coordination Ag-O 7’ from a phosphodiester group of an adjacent complex. Attempts were made to access and isolate single Ag-chains from crystalline material by mechanical exfoliation techniques. Sonication (in hexane) yielded a uniform distribution of 2D flakes that were 3.0 nm in height. Powder X-ray diffraction results suggested that the cleavage likely occurred at the Ag-O 7’ position resulting in flakes with a bilayer of Ag-chains running perpendicular to the substrate in the [101] direction. Cytosine rich oligonucleotides were investigated as a controlled method of accessing stabilised few atom metallic clusters or particles. Oligonucleotides were designed with a non-binding central region, which allowed folding into a hairpin type secondary structure facilitated by C Ag-C coordination. A novel approach to controlled metal ion capture was investigated. A focus was placed on loop and stem optimisation utilising mass spectroscopy, circular dichroism and isothermal titration calorimetry techniques. It was discovered that oligos required central non binding looped regions of at least two units to retain sufficient flexibility for the folding of the oligo. The abilities to capture or populate the free mismatched cytosine-cytosine mediation sites with Ag+ decreased as the length and number of mismatched C-C sites increased. This was due to increased conformational flexibility and cooperativity effects. We were able to maximise the Ag+ occupancy for oligonucleotides with six or less C-C mismatched sites.