Synthesis and Structure−DNA Binding Relationship Analysis of DNA Triple-Helix Specific Intercalators

Strękowski, Lucjan; Gulevich, Yuri; Tc, Baranowski; An, Parker; As, Kiselyov; Lin, Shuo; Fa, Tanious; Wilson, W. David

doi:10.1021/jm9603734

Cited by 29 publications

(18 citation statements)

References 16 publications

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“…Compound 1 (42), is 4-(4-methylpiperazino-2-(2-naphthyl)quinoline and was obtained from Sigma-Aldrich (Milwaukee, WI, USA). Compound 2 is 1-phenyl-4-pyrrolidino-2,3-dihydro-1/H/-pyrrolo[2,3-/b/]quinoline and was obtained from Chemical Block (N.D. Zelinsky Institute of Organic Chemistry, Moscow, Russia).…”

Section: Methodsmentioning

confidence: 99%

Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform

Holt

Ragazzon

Strękowski

et al. 2009

Nucleic Acids Research

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Virtual Screening is an increasingly attractive way to discover new small molecules with potential medicinal value. We introduce a novel strategy that integrates use of the molecular docking software Surflex with experimental validation by the method of competition dialysis. This integrated approach was used to identify ligands that selectively bind to the triplex DNA poly(dA)-[poly(dT)]2. A library containing ∼2 million ligands was virtually screened to identify compounds with chemical and structural similarity to a known triplex intercalator, the napthylquinoline MHQ-12. Further molecular docking studies using compounds with high structural similarity resulted in two compounds that were then demonstrated by competition dialysis to have a superior affinity and selectivity for the triplex nucleic acid than MHQ-12. One of the compounds has a different chemical backbone than MHQ-12, which demonstrates the ability of this strategy to ‘scaffold hop’ and to identify small molecules with novel binding properties. Biophysical characterization of these compounds by circular dichroism and thermal denaturation studies confirmed their binding mode and selectivity. These studies provide a proof-of-principle for our integrated screening strategy, and suggest that this platform may be extended to discover new compounds that target therapeutically relevant nucleic acid morphologies.

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Section: Methodsmentioning

confidence: 99%

Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform

Holt

Ragazzon

Strękowski

et al. 2009

Nucleic Acids Research

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“…Naphthylquinoline derivatives, Fig (7 ) also selectively bind to triplex DNA by intercalation [119][120][121][122][123]. These compounds possess a large aromatic area to stack with the three bases in the triplex, yet, since the aromatic portions are not fused, they possess torsional flexibility and can accommodate the propeller twist of the triplets in which the three bases may not be coplanar.…”

Section: Tethered Dna Binding Agentsmentioning

confidence: 99%

Targeting DNA with Triplexes

Fox¹

2000

CMC

192

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The formation of intermolecular DNA triple helices offers the possibility of designing compounds with extensive sequence recognition properties which may be useful as antigene agents or tools in molecular biology. In these structures a third strand oligonucleotide binds in the DNA major groove, making specific contacts with substituents on the exposed faces of the base pairs. Although triplexes form with exquisite specificity their use suffers from several drawbacks. Two limitations of this approach, which are considered in this review are, firstly that conditions of low pH are necessary for formation of the C+*GC triplet, and secondly that these structures are often less stable than their duplex counterparts. This review outlines the strategies that have been employed to overcome these drawbacks. The pH problem is addressed by considering the various DNA base analogues that have been used to recognise GC base pairs in a pH independent fashion, and discusses the benefits and limitations of each analogue. Triplex stability can be increased by using novel base analogues, backbone modifications and the use of triplex-specific binding ligands.

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“…52 One of the most selective and extensively studied classes are the napthylquinolines, which have been shown to intercalate into the TAT DNA triplex, poly(dA)-[poly(dT)] 2 . [53][54][55][56] Chaires et al performed an extensive study that characterized the selectivity and affinity of 14 napthylquinoline derivatives with the aid of the newly developed competition dialysis assay (Fig. 5).…”

Section: Targeting Triplex Dna By Small Moleculesmentioning

confidence: 99%

Recognition and regulation of unique nucleic acid structures by small molecules

Song

Ren

2010

Chem. Commun.

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DNA and RNA are both polymorphic. Depending on the sequences and environmental conditions, they could exist in a variety of secondary structures that play key roles in many biological processes. Recognition of these structures by small ligands is very important for the development of new drugs and new tools. In this article, we will focus on recent advances in the field of molecular recognition and regulation of small ligands with several unique nucleic acid structures, and we will also highlight some of their potential applications in medicinal chemistry and biotechnology.

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Synthesis and Structure−DNA Binding Relationship Analysis of DNA Triple-Helix Specific Intercalators

Cited by 29 publications

References 16 publications

Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform

Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform

Targeting DNA with Triplexes

Recognition and regulation of unique nucleic acid structures by small molecules

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