Targeting DNA through covalent interactions of reversible binding drugs

Graves, David E.

doi:10.1016/s0076-6879(01)40432-0

Cited by 7 publications

(3 citation statements)

References 77 publications

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“…Similarly, genistein and quinolones are also non-intercalative [101,[123][124][125]129]. In contrast, amsacrine, doxorubicin, and mitoxantrone are all intercalative in nature, and the latter two compounds bind DNA with very high affinities [130][131][132]. It was originally thought that topoisomerase II-targeted drugs acted through interactions with DNA, "highjacking" the enzyme to sites of drug binding.…”

Section: Non-covalent Topoisomerase II Poisonsmentioning

confidence: 99%

DNA topoisomerase II, genotoxicity, and cancer

McClendon

Osheroff

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

361

466

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Type II topoisomerases are ubiquitous enzymes that play essential roles in a number of fundamental DNA processes. They regulate DNA under-and overwinding, and resolve knots and tangles in the genetic material by passing an intact double helix through a transient double-stranded break that they generate in a separate segment of DNA. Because type II topoisomerases generate DNA strand breaks as a requisite intermediate in their catalytic cycle, they have the potential to fragment the genome every time they function. Thus, while these enzymes are essential to the survival of proliferating cells, they also have significant genotoxic effects. This latter aspect of type II topoisomerase has been exploited for the development of several classes of anticancer drugs that are widely employed for the clinical treatment of human malignancies. However, considerable evidence indicates that these enzymes also trigger specific leukemic chromosomal translocations. In light of the impact, both positive and negative, of type II topoisomerases on human cells, it is important to understand how these enzymes function and how their actions can destablize the genome. This article discusses both aspects of human type II topoisomerases.

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Section: Non-covalent Topoisomerase II Poisonsmentioning

confidence: 99%

DNA topoisomerase II, genotoxicity, and cancer

McClendon

Osheroff

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

361

466

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“…Small molecule bio‐sensors can be involved in a variety of interactions with macro‐biomolecules such as nucleic acids, including intercalation (π‐π interaction) between the base pairs, [13] covalent, [14] noncovalent, hydrophobic, or electrostatic interactions [4] . Three different binding mechanisms are typically involved when the probes interact with DNA: (i) electrostatic interaction, (ii) groove binding, and (iii) intercalative binding.…”

Section: Introductionmentioning

confidence: 99%

An Emission‐Based Probe for the Detection and Quantification of DNA and RNA

Adak,

Rahaman,

Karmakar

et al. 2024

Chemistry An Asian Journal

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Sequence‐independent detection of low concentrations of nucleic acids is important for applications in forensics and diagnostics. An emission‐based probe for detecting and quantifying DNA and RNA utilizing a water‐soluble dicationic tetraphenylethene (TPE) derivative was developed. The recognition is based on the electrostatic and other non‐covalent interactions between the phosphate backbone of nucleic acids and the cationic probe, which cause the restriction of rotation of the aryl units of the probe, ensuing in the enhancement of the fluorescence signal. The binding was validated by different spectroscopic techniques and also by electrophoretic mobility shift assay. The probable mode of binding with the nucleic acids was studied by blind‐docking studies that correlated well with the experimental results.

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“…Forty years ago, this compound served to seal the hydrodynamic basis of the DNA intercalation model and contributed to the measure of DNA supercoiling (19)(20)(21)(22). Over the past four decades, its DNA/RNA intercalative binding properties have been thoroughly investigated by a multitude of techniques, including X-ray diffraction (23,24), fluorescence (25)(26)(27), NMR (28)(29)(30)(31), spectrophotometry (32), equilibrium dialysis (33)(34)(35), stopped-flow (36), calorimetry (37)(38)(39)(40), polarimetric (41) and electrooptical methods (42,43), linear dichroism (44,45), molecular modeling (46), DNase I footprinting (47), photoaffinity (48,49), chemical cross-linking (50), topoisomerase-based assays (51), and many other gel-based and physicochemical and spectroscopic methods.…”

mentioning

confidence: 99%

Molecular Determinants for DNA Minor Groove Recognition: Design of a Bis-Guanidinium Derivative of Ethidium That Is Highly Selective for AT-Rich DNA Sequences

et al. 2005

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The phenanthridinium dye ethidium bromide is a prototypical DNA intercalating agent. For decades, this anti-trypanosomal agent has been known to intercalate into nucleic acids, with little preference for particular sequences. Only polydA-polydT tracts are relatively refractory to ethidium intercalation. In an effort to tune the sequence selectivity of known DNA binding agents, we report here the synthesis and detailed characterization of the mode of binding to DNA of a novel ethidium derivative possessing two guanidinium groups at positions 3 and 8. This compound, DB950, binds to DNA much more tightly than ethidium and exhibits distinct DNA-dependent absorption and fluorescence properties. The study of the mode of binding to DNA by means of circular and electric linear dichroism revealed that, unlike ethidium, DB950 forms minor groove complexes with AT sequences. Accurate quantification of binding affinities by surface plasmon resonance using A(n)T(n) hairpin oligomer indicated that the interaction of DB950 is over 10-50 times stronger than that of ethidium and comparable to that of the known minor groove binder furamidine. DB950 interacts weakly with GC sites by intercalation. DNase I footprinting experiments performed with different DNA fragments established that DB950 presents a pronounced selectivity for AT-rich sites, identical with that of furamidine. The replacement of the amino groups of ethidium with guanidinium groups has resulted in a marked gain of both affinity and sequence selectivity. DB950 provides protection against DNase I cleavage at AT-containing sites which frequently correspond to regions of enhanced cleavage in the presence of ethidium. Although DB950 maintains a planar phenanthridinium chromophore, the compound no longer intercalates at AT sites. The guanidinium groups of DB950, just like the amidinium group of furamidine (DB75), are the critical determinants for recognition of AT binding sites in DNA. The chemical modulation of the ethidium exocyclic amines is a profitable option to tune the nucleic acid recognition properties of phenylphenanthridinium dyes.

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Targeting DNA through covalent interactions of reversible binding drugs

Cited by 7 publications

References 77 publications

DNA topoisomerase II, genotoxicity, and cancer

DNA topoisomerase II, genotoxicity, and cancer

An Emission‐Based Probe for the Detection and Quantification of DNA and RNA

Molecular Determinants for DNA Minor Groove Recognition: Design of a Bis-Guanidinium Derivative of Ethidium That Is Highly Selective for AT-Rich DNA Sequences

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