The relationship between ligand aggregation and G-quadruplex DNA selectivity in a series of 3,4,9,10-perylenetetracarboxylic acid diimides.

摘要: Human telomeres are comprised of d(TTAGGG) repeats that capable forming G-quadruplex DNA structures. Ligands bind to and stabilize these structures potential inhibitors the cancer cell-associated enzyme telomerase. Other biological uses targeting ligands have been proposed. One particularly challenging aspect contemplated is their selectivity for versus double-stranded We previously reported observation two structurally related 3,4,9,10-perylenetetracarboxylic acid diimide-based ligands, PIPER [N,N'-bis(2-(1-piperidino)ethyl)-3,4,9,10-perylenetetracarboxylic diimide] Tel01 [N,N'-bis(3-(4-morpholino)propyl)-3,4,9,10-perylenetetracarboxylic diimide], different levels binding at pH 7 as determined by absorbance changes in presence [Kerwin, S. M., Chen, G., Kern, J. T., Thomas, P. W. (2002) Bioorg. Med. Chem. Lett. 12, 447-450]. Here we report less selective ligand can unwind double-stranded, closed circular plasmid DNA, a topoisomerase I assay. A model interaction with structure formed d(TAGGGTTA) was from NMR experiments. This similar published bound same failed provide structural basis observed increased DNA. In contrast, investigation into aggregation state well other diimide analogues bearing basic side chains demonstrates correlated selectivity. For all six examined, those were aggregated 70 mM potassium phosphate, 100 KCl, 1 EDTA buffer also demonstrated under conditions. not conditions display much lower The extremely sensitive pH. Tel01, which 7, 6.4, where it only modest selectivity, 8.5 both highly DNA-selective. To our knowledge, studies demonstrate first achieved through pH-mediated aggregation. impact findings on classes discussed.