Recognition of DNA secondary structures, which contain non-canonical thymines, using coordination complexes will be presented. A library of Zn(II) complexes that selectively bind to biologically relevant DNA secondary structures, including G-quadruplexes and thymine bulges, was constructed. All of the complexes contain a cyclen (1,4,7,10-tetraazacyclododecane) macrocycle complexed with Zn(II) that forms a coordination bond with the deprotonated imine nitrogen (N3) of thymine. The inclusion of an aromatic pendent on the Zn(II)-cyclen complex improves binding through a π-π stacking interaction between the pendent and thymine aromatic face. The aromatic pendents presented consist of either two- or three-fused aromatic rings that are appended to the conserved Zn(II)-cyclen moiety. These pendents include: quinolinone (ZnMQC), quinoline (ZnCQC) and anthraquinone (ZnATQ). This library of bifunctional complexes is used to investigate the contribution of the aromatic group in binding to non-canonical thymines in different structural contexts, similar to those found in thymine-containing bulges and G-quadruplex loops. Binding to duplex, bulged and G-quadruplex DNA was characterized using: surface plasmon resonance (SPR; Fig.1A), isothermal calorimetery (ITC; Fig.1B) and fluorescent spectroscopy. Favorable binding in the range of 14 μM to 22 μM to a thymine bulge was observed for ZnATQ and ZnCQC. Selectivity for the thymine bulge was demonstrated with weak binding to a similar cytosine bulge. However, all complexes were shown to bind tightly (&lt; 6.0 μM) to H-Telo using a 2:1 stoichiometry and a 3:1 stoichiometry as shown for ZnATQ. The ZnMCC, ZnCQC and ZnATQ stabilize H-Telo by increasing the melting temperature by 9 ℃.

Selective recognition of G-quadruplex and thymine bulge DNA using bifunctional Zn(II) complexes

249th National Meeting (2015)

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