The influence of intercalator binding on DNA triplex stability: correlation with effects on A‐tract duplex structure

Abstract

The triplex form of DNA is of interest because of a possible biological role as well as the potential therapeutic use of this structure. In this paper the stabilizing effects of two intercalating drugs, ethidium and the quinoxaline derivative 9-OH-B220, on DNA triplexes have been studied by thermal denaturation measurements. The corresponding duplex structures of the DNA triplex systems investigated are either A-tract or normal B-DNA. The largest increases in the triplex melting temperatures caused by the intercalators were found for sequences having A-tract duplex structures. Inserting a single base pair with an N2-amino group in the minor groove, e.g. a G-C pair, breaks up the A-tract duplex structure and also reduces the stabilizing effect of the drugs on the triplex melting temperatures. The large drug-induced increase in triplex melting temperature for complexes having an original duplex A-tract structure is correlated with a low initial melting point of the triplex, not with the triplex being unusually stable in the presence of the drug. Hence, we conclude that the large thermal stabilizing effect exhibited by ethidium and 9-OH-B220 on dTn.dAn-dTn triplexes is partly caused by the intercalators breaking up the intrinsic A-tract structure of the underlying duplex.

Understanding the structural and dynamic consequences of DNA epigenetic modifications: Computational insights into cytosine methylation and hydroxymethylation

“…32,33 We have previously shown that continuous major groove methylation affects both the structure and dynamics of dsDNA by improving base stacking and probably also by modulating water binding. [34][35][36] Thus, it might be of significance that methylation of d(CGCGAATTCGCG) 2 at position 9 creates a 6 bases long spine of major groove methyl groups, that double-methylation at positions 3 and 9 provides 8 consecutive methyl groups, and that the methyl group afforded by single methylation at position 3 remains isolated (Fig.…”

Structure-Based DNA-Targeting Strategies with Small Molecule Ligands for Drug Discovery

“…Since the TFO naturally exists in biological systems, therefore, the TFO itself can also serve as a therapeutic target for novel drug development. Actually, most of the previously mentioned DNA intercalators can also bind and stabilize the triplex system due to their planar structure, though the selectivity is expected to be low. Moreover, Arya and co‐workers have presented an alternative method to recognize the DNA triplex using aminosugar compounds.…”

Binding of protoberberine alkaloid coralyne with double stranded poly(A): a biophysical study

“…It is suggested that coralyne intercalates T*AÁT triple helices, disproportionates duplex poly(dT)Ápoly(dA) into triplex poly(dT)*poly(dA)Ápoly(dT), forms self structures with poly(dA) molecules and stabilizes triplexes. [44][45][46][47] Homo adenine aggregation occurs in the presence of this alkaloid 48 and is supported further by the formation of self-structured poly(A). 23 Recently, the photoinduced DNA damaging phenomenon of coralyne has also been reported.…”