Stabilization of DNA triple helices by a series of mono- and disubstitutedamidoanthraquinones

We have used quantitative DNase I footprinting to measure the relative affi nities of four disubstituted and two monosubstituted amidoanthraquinone com pounds for intermolecular DNA triplexes, and have examined how the position of the attached base-functionalized substituents affects their ability to stabilize DNA triplexes. All four isomeric disubstituted derivatives examin ed stabilize DNA triplexes at micromolar or lower concentrations. Of the co mpounds studied the 2,7-disubstituted amidoanthraquinone displayed the grea test tripler affinity. The order of tripler affinity for the other disubsti tuted ligands decreases in the order 2,7 > 1,8 = 1,5 > 2,6, with the equiva lent monosubstituted compounds being at least an order of magnitude less ef ficient. The 1,5-disubstituted derivative also shows some interaction with duplex DNA. These results have been confirmed by molecular modelling studie s, which provide a rational basis for the structure-activity relationships. These suggest that, although all of the compounds bind through an intercal ative mode, the 2,6, 2,7 and 1,5 disubstituted isomers bind with their two side groups occupying adjacent tripler grooves, in contrast with the 1,8 is omer which is positioned with both side groups in the same tripler groove.