Binding of unfused aromatic cations to DNA.  The influence of molecular twist on intercalation

Wilson, W. David; Strękowski, Lucjan; Tanious, Farial A.; Watson, R. A.; Mokrosz, Jerzy L.; Strekowska, A; Webster, Gordon; Neidle, Stephen

doi:10.1021/ja00233a003

Cited by 54 publications

(71 citation statements)

References 2 publications

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“…We have shown in a previous crystal structure that a phenyl-pyridine type junction, such as that in DB1164, has a twist angle between 10°-20° in the solid state. 45 The lower torsional angle is presumably due to single proton pair repulsion as versus two similar repulsions in biphenyl type systems. Based on extension of these results, the angle for the phenyl-pyrimidine system of DB1242, with no proton pair repulsion, would be expected to be near 0° and Hartree-Fock calculations support this hypothesis.…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

Design of DNA Minor Groove Binding Diamidines That Recognize GC Base Pair Sequences: A Dimeric-Hinge Interaction Motif

et al. 2007

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The classical model of DNA minor groove binding compounds is that they should have a crescent shape that closely fits the helical twist of the groove. Several compounds with relatively linear shape and large dihedral twist, however, have been found recently to bind strongly to the minor groove. These observations raise the question of how far the curvature requirement could be relaxed. As an initial step in experimental analysis of this question, a linear triphenyl diamidine, DB1111 and a series of nitrogen tricyclic analogues were prepared. The goal with the heterocycles is to design GC binding selectivity into heterocyclic compounds that can get into cells and exert biological effects. The compounds have a zero radius of curvature from amidine carbon to amidine carbon but a significant dihedral twist across the tricyclic and amidine-ring junctions. They would not be expected to bind well to the DNA minor groove by shape-matching criteria. Detailed DNaseI footprinting studies of the sequence specificity of this set of diamidines indicated that a pyrimidine heterocyclic derivative, DB1242, has remarkable binding specificity for a GC rich sequence, -GCTCG-. It binds to the GC sequence more strongly than to the usual AT recognition sequences for curved minor groove agents. Other similar derivatives did not exhibit the GC specificity. Biosensor-surface plasmon resonance and isothermal titration calorimetry experiments indicate that DB1242 binds to the GC sequence as a highly cooperative stacked dimer. Circular dichroism results indicate that the compound binds in the minor groove. Molecular modeling studies support a minor groove complex and provide an inter-compound and compound-DNA hydrogen bonding rational for the unusual GC binding specificity and the requirement for a pyrimidine heterocycle. This compound represents a new direction in development of DNA sequence specific agents and it is the first non-polyamide, synthetic compound to specifically recognize a DNA sequence with a majority of GC base pairs.

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Section: Molecular Docking Studiesmentioning

confidence: 99%

Design of DNA Minor Groove Binding Diamidines That Recognize GC Base Pair Sequences: A Dimeric-Hinge Interaction Motif

et al. 2007

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“…Several classes of DNA-binding compounds have been identified as BLM amplifiers at a low ratio of compound: DNA-P. These are polyamines (Strekowski et al, 1988a), such as 1-3, classical DNA intercalators (Agostino et al, 1984;Pavelic et al, 1985;Strekowski et al, 1987a), such as ethidium, 4, non-classical DNA intercalators (Strekowski et al, 1987a(Strekowski et al, , 1988bWilson et al, 1988Wilson et al, , 1989, such as 5 and 6, and groove binding compounds (Wilson et al, 1988), such as 7 (Fig. 2).…”

Section: Blm-a5 R = Nh(ch)nh; (Ch)nhj; Blm-a6 R =mentioning

confidence: 99%

“…This reduction can be achieved in the presence of an organic reductant, such as thiol, in a disproportionation reaction of two bleomycin complexes, or in a bimolecular collision between the bleomycin complex and ferrous ion (Strekowski et a[., 1988~). The activated bleomycin thus obtained, binds with and causes degradation of DNA, with the release of small DNA fragments, and inactive BLM.Fe(II1) complex.…”

Section: Binding Of Bleomycin With Dnamentioning

confidence: 99%

“…These compounds are comprised of unfused heteropolyaromatic systems with flexible cationic substituents (Strekowski et al, 1988b;Wilson et al, 1988Wilson et al, , 1989. Although these derivatives are structurally related to the bithiazole fragment of bleomycin, their effect on the bleomycin degradation differs strikingly from that of the bithiazole.…”

Section: Bleomycin Amplificationmentioning

confidence: 99%

See 1 more Smart Citation

Molecular basis for potentiation of bleomycin‐mediated degradation of DNA by polyamines. Experimental and molecular mechanical studies

Strękowski¹,

Harden²,

Wydra³

et al. 1989

J of Molecular Recognition

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The bleomycin-mediated degradation of DNA is stimulated (amplified) by certain DNA binding compounds, such as polyamines, that distort the double helix. Computer modelling studies suggest that putrescine (1), spermidine (2), and spermine (3) bind preferentially on the floor of the major groove of (dGdC)5.(dGdC)5. This interaction results in a bend of the oligomer helix toward the major groove and enlargement of the minor groove, both effects being in the order 1 less than 2 less than 3. These polyamine-induced distortions, as obtained from theoretical studies, parallel the experimental values of the amplification activities of 1-3 in the bleomycin-mediated degradation of poly(dGdC).poly(dGdC). The amplification mechanism of non-competitive binding of amplifier molecules in the major groove, and bleomycin in the minor groove, is proposed. It is suggested that the amplifier-induced conformational changes of the DNA helix increase affinity of the activated bleomycin complex toward the DNA minor groove and, consequently, result in an increased efficiency of the bleomycin-mediated degradation of the helix.

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“…Seeking to identify drugs that would enhance the antitumor activity of the DNA groove-binding drug bleomycin, they discovered that DNA intercalators could alter the topology of a naked DNA molecule in such a way as to enhance the DNA double-strand nicking activity of bleomycin [Strekowski et al, 1987[Strekowski et al, , 1991Wilson et al, 1988Wilson et al, , 1990Strekowski, 1992]. A variety of other mechanisms that could account for bleomycin amplification aside from DNA intercalation were also discussed in these studies.…”

Section: Noncovalent Dna Interactionmentioning

confidence: 99%

Toward a greater appreciation of noncovalent chemical/DNA interactions: Application of biological and computational approaches

Snyder¹,

Hendry²

2005

Environ and Mol Mutagen

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Noncovalent DNA interactions, e.g., DNA intercalation and DNA groove-binding, have not been well studied relative to covalent interactions largely due to the inability of predicting and detecting such events in intact cells. We have adapted an in vitro bleomycin amplification method for DNA intercalation for use in cultured V79 Chinese hamster cells and have validated this approach through the use of a three-dimensional DNA computational docking model that quantifies potential strength of DNA intercalative binding based on electrostatics and hydrogen bonding. For many structural classes of molecules, DNA intercalation is necessary but not sufficient for genotoxicity. The present article reviews our progress to date in predicting and confirming noncovalent binding of drugs and other chemicals and in understanding the mechanistic relationship between intercalation and genotoxicity.

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Binding of unfused aromatic cations to DNA. The influence of molecular twist on intercalation

Cited by 54 publications

References 2 publications

Design of DNA Minor Groove Binding Diamidines That Recognize GC Base Pair Sequences: A Dimeric-Hinge Interaction Motif

Design of DNA Minor Groove Binding Diamidines That Recognize GC Base Pair Sequences: A Dimeric-Hinge Interaction Motif

Molecular basis for potentiation of bleomycin‐mediated degradation of DNA by polyamines. Experimental and molecular mechanical studies

Toward a greater appreciation of noncovalent chemical/DNA interactions: Application of biological and computational approaches

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