Structure-dependent effects of minor groove binders on the DNA triple helix motif poly(dA).2poly(dT): influence of antitumoractive nonintercalative bisquaternary ammonium heterocycles.
The interaction of a series of bisquaternary ammonium heterocycles (BQA) with the triple helix of poly(dA).2poly(dT) was investigated using thermal denaturation and circular dichroism spectroscopy. The BQA-bound triplexes undergo two distinct transitions during thermal melting: a first melting step from the triplex to the duplex state with the BQA ligand remaining bound and a second step from the duplex to single strands. The ionic strength dependence of the triplex stability at increasing ligand concentration was analyzed by phase diagrams. The results demonstrate that some BQA ligands thermally stabilize the triplex at Na+ concentrations of < or = 150 mM and destabilize this structure above the range 150-220 mM Na+, indicating promotion of triplex formation under low ionic strength and diminution of the affinity of the major groove-bound third strand in the triplex at high ionic strength. SN-6999 most strongly destabilizes the triplex structure but stabilizes the DNA duplex, while SN-16814 showed no effect at all on the triplex stability. In contrast, SN-18071 exclusively promotes triplex formation and is the most potent triplex stabilizer of the BQA ligands investigated, which is also more effective than spermine. The differential triplex-stabilizing and -destabilizing effects of BQA ligands are discussed on the bases of variations in their DNA binding properties.
Abteilung Molekulare Biologie, Institut für Molekularbiologie der Friedrich-Schiller, Universität Jena, Germany.
I
I
Förtsch
B
B
Baguley
C
C
Zimmer
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D008024:Ligands; D009691:Nucleic Acid Denaturation; D011089:Polydeoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013696:Temperature
D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D008024:Ligands; D011089:Polydeoxyribonucleotides; D000644:Quaternary Ammonium Compounds; C093830:poly(dT)-2poly(dA); D004247:DNA