Probing the Properties of Zn Complexes for the Cleavage of Phosphate Diesters and the Influence of Non-covalent Assembly

The design of artificial catalysts to hydrolyse phosphate diesters under mild conditions remains extremely challenging. In particular, dissecting and quantifying the interactions that lead to efficient catalysis has yet to be achieved fully to allow the complete understanding of current catalysts. Furthermore, the use of weak, supramolecular interactions to influence and control the activity of these catalysts remains a challenge, despite the central role that these interactions play in natural systems.
This work focuses on catalysing the hydrolysis of DNA- and RNA-like substrates with mono- and dinuclear zinc complexes. Particular attention is given to quantifying the effect of varying structural features on kinetic activity and to study the impact of organic groups that affect the microenvironment and potential assembly of these complexes.
The activity of a series of dinuclear zinc complexes is separated into ground and transition state effects to understand the impact of changing peripheral ligand substituents in cleaving RNA-like substrates. The presence of amino functionalities (NH2 and NHMe) in the vicinity of the metal ions resulted in a 30-fold increase in ground state binding and 40 to 130-fold increase in transition state stabilisation compared to the parent complex. The role of headgroup is explored, and an unexpected sensitivity to reversible inhibition by carbon dioxide discovered.
To introduce aggregation of mononuclear complexes through non-covalent interactions, ligands with hydrophobic anchors were synthesised so that they could be embedded into vesicles. No evidence for an increase in activity through aggregation was observed, but a medium effect in cationic vesicles enhanced the activity of the catalytic centre by more than an order of magnitude (3.6 ± 0.4 M-1 s-1) relative to the reactivity in more polar aqueous environment (0.16 ± 0.01 M-1 s-1).
More specific structural organisation of the same zinc complex was attempted through the conjugation of peptides that were designed to assemble into dimers, but the observed activity reflected that of the monomeric species. Structural characterisation suggested that although the peptides did form the anticipated secondary structure, intermolecular association did not occur to an appreciable extent.
Finally, the effect of varying the structures of alcohol and oxime nucleophiles covalently incorporated into zinc complexes was explored. The introduction of methyl groups close to the nucleophilic centre led to significant changes in solution properties, but approximately 3-fold lower reactivity towards DNA-like substrates.