Chiral lanthanide complexes as probe of nucleic acids

Abstract

A series of kinetically stable chiral lanthanide complexes has been developed, with a view to developing responsive probes for use in analysis and in seeking chiral complexes exhibiting selectivity in their interaction with nucleic acids. Firstly a pH sensitive complex has been modified with the aim of tuning the pH range to which it responds to the physiologically useful regime. The synthesis was undertaken of relatively lipophilic 6-butylphenanthridinyl complexes. Their photophysical behaviour was investigated by absorbance and luminescence spectroscopy and the modulation of their emission examined in the pH range 4.5 to 7.5.In addition to their luminescent properties, enantiomerically pure chiral lanthanide complexes permit chiroptical techniques to be used, allowing their interactions with other chiral species to be addressed (e.g. nucleic acids, oligonucleotides).The first series of enantiopure lanthanide complexes has been devised that show several interesting features in binding to oligonucleotides and nucleic acids. These macrocyclic tris-and tetra-amide lanthanide (Eu, Tb or Yb) complexes contain an N-alkyl phenanthridinium unit that allows intercalation between the base pairs of the DNA. Their binding to [(AT)(_6)](_2), [(CG)(_6)](_2) and CT-DNA was monitored by changes in the ligand and metal based luminescence, and in the characteristic CD bands of the oligonucleotides. Binding affinities were assessed using intrinsic methods and the McGhee-von Hippel analysis. Marked differences have been observed in the binding of Eu and Yb complexes as a function of the A and Δ helicity of the complexes, which is itself determined by the configuration of the remote amide substituents. Binding of the A-Eu complex was over 50 times stronger to [(CG)(_6)](_2) compared to [(AT)(_6)](_2), while the left handed Δ-Yb complex showed a different pattern of selectivity. In the europium complex of a related heptadentate tris-amide ligand, the coordination of a DNA phosphate group to the lanthanide centre was suggested by emission and lifetime changes. Another series of chiral tetraamide complexes linked to the 6 position of the phenanthridine moiety was synthesised and studied. An additional stereogenic centre at carbon, alpha to the phenanthridine group was introduced with the aim of tuning the selectivity of binding. A set of four diastereoisomeric ligands was separated and their lanthanide complexes characterised. The binding of their Eu and Yb complexes was evaluated and differences between Eu and Yb complexes persisted. The additional chiral centre did not appear to modify the binding affinity of this series of complexes. Finally, a series of 6-phenanthridinyl complexes was investigated in which the phenanthridine N atom was directly bound to the lanthanide centre. Their affinity for DNA was found to be relatively low, which may be related to their rigid structure.