STRUCTURE-DEPENDENT EFFECTS OF MINOR-GROOVE BINDERS ON THE DNA TRIPLE-HELIX MOTIF POLY(DA)CENTER-DOT-2POLY(DT) - INFLUENCE OF ANTITUMORACTIVE NONINTERCALATIVE BISQUATERNARY AMMONIUM HETEROCYCLES

The interaction of a series of bisquaternary ammonium heterocycles (BQ A) with the triple helix of poly(dA).2poly(dT) was investigated using thermal denaturation and circular dichroism spectroscopy. The BQA-boun d triplexes undergo two distinct transitions during thermal melting: a first melting step from the tripler to the duplex state with the BQA ligand remaining bound and a second step from the duplex to single str ands. The ionic strength dependence of the tripler stability at increa sing ligand concentration was analyzed by phase diagrams. The results demonstrate that some BQA ligands thermally stabilize the triplex at N a+ concentrations of less than or equal to 150 mM and destabilize this structure above the range 150-220 mM Na+, indicating promotion of tri pler formation under low ionic strength and diminution of the affinity of the major groove-bound third strand in the tripler at high ionic s trength. SN-6999 most strongly destabilizes the tripler structure but stabilizes the DNA duplex, while SN-16814 showed no effect at all on t he tripler stability. In contrast, SN-18071 exclusively promotes tripl er formation and is the most potent tripler stabilizer of the BQA liga nds investigated, which is also more effective than spermine. The diff erential tripler-stabilizing and -destabilizing effects of BQA ligands are discussed on the bases of variations in their DNA binding propert ies.