NMR Kinetic Measurements in DNA Folding and Drug Binding

DNA quadruplex structures have been of considerable interest as supramolecular self-assembling systems [1] and because of their potential biological importance in the regulation of a variety of processes within the cell cycle including replication, transcription, and recombination [2]. The observation that the telomeric repeats at the ends of chromosomes (5′-TTAGGG in humans) are able to assemble in the presence of monovalent cations into folded structures containing stacked G-tetrads has bought them into focus as a drug target, notably to interfere with telomere maintenance in immortalized human tumorderived cell lines by inhibiting the enzyme telomerase [1-6]. The novel fluorinated polycyclic quinoacridinium cation RHPS4 (Figure la) shows enhanced binding to higher-ordered DNA structures (triplex/quadruplex) and is a potent inhibitor of telomerase function [7,8]. To investigate the drug-quadruplex interaction, as part of a rational ligand design approach, we have studied by NMR the structure (Figure lb) and dynamics of the RHPS4 complex with the intermolecular parallel-stranded quadruplex d(TTAGGGT)₄, formed from the human telomeric repeat [9,10].