Theoretical studies of the intercalation of 9-hydroxyellipticine in DNA

Elcock, Adrian H.; Rodger, Alison; Richards, W. Graham

doi:10.1002/(sici)1097-0282(199609)39:3<309::aid-bip4>3.0.co;2-s

Cited by 14 publications

(12 citation statements)

References 53 publications

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“…This statement seems to be in partial agreement with the report by Elcock et al who studied the binding of 9-hydroxyellipticine into poly(AT) DNA and obtained a structure of intercalative complex with the pyridine nitrogen oriented into the major groove, however, on the basis of quite short MD simulations. The orientation of the pyrrole nitrogen was not clearly specified, and as discussed in ref the resulting structure was stabilized by the interaction of the hydroxyl group with water in the minor groovean interaction that cannot occur with ellipticine lacking the hydroxyl group. In addition, the pyridine nitrogen in our simulations tends to be oriented close to the edge of the major groove, creating a hydrogen bond with the O4′ atom of one of the sugars in the backbone occasionally.…”

Section: Resultssupporting

confidence: 91%

“…On the basis of the calculated entropic and enthalpic changes, we suggest the “int1” orientation of ellipticine (with the pyrrole nitrogen atom oriented toward the major groove) to be more stable than the “int2” orientation. Taking also previous results of X-ray experiments and MD simulations ,, into account, our results indicate that the actual binding motif is certainly dependent not only on the chemical identity of the ligand but also on the targeted sequence.…”

Section: Discussionsupporting

confidence: 70%

“…Ellipticine (Figure ) is a plant alkaloid with antitumor activity, which has been the object of many experimental and theoretical studies concerning its activity, sequence selectivity, and metabolism; various ellipticine derivatives have been studied as well. − As an intercalator, it exhibits a lower sequence specificity as compared to minor-groove binders; the pyrimidine−purine steps are slightly preferred because of their larger flexibility . The first experimental evidence of the interaction of ellipticine with a DNA-like structure was given by Jain et al who obtained a crystal of ellipticine bound to two dinucleoside monophosphates .…”

Section: Introductionmentioning

confidence: 99%

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Sequence-Dependent Configurational Entropy Change of DNA upon Intercalation

2010

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We investigated the intercalation of an antitumor drug ellipticine into four adenine-thymine (AT) rich DNA duplexes with the focus on the configurational entropy, by means of molecular dynamics (MD) simulations. Two possible binding orientations of ellipticine in a DNA double helix were studied, and the orientation with the pyrrole nitrogen exposed into a major groove was identified as the more probable. The configurational entropy change of DNA is shown to contribute significantly to the binding free energy. The magnitude of this contribution depends on the exact DNA sequence. A detailed analysis revealed that the largest flexibility changes occurred in the sugar-phosphate backbone, resulting in an entropy gain in the most cases. The nucleobases were not involved in the changes of flexibility and entropy. BI/BII-like conformational transitions were observed after the intercalation of ellipticine, and the consequences of these transitions for the evaluation of entropy are discussed.

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Section: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

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Sequence-Dependent Configurational Entropy Change of DNA upon Intercalation

2010

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“…Much of research work on ellipticine is focused on its biological activity, sequence selectivity, and metabolism. − Very few photophysical studies have so far been performed on this system. ,,− As ellipticine and its derivatives can exist in different prototropic forms, understanding the influence of environment on the prototropic equilibria is extremely important from the point of view of understanding the photophysical behavior of the system, which, in turn, can help monitor the transport of ellipticine to its target and its uptake and release by/from the carrier, Chen and co-workers recently studied the solvent effect on the photophysical properties of ellipticine . In this work, which involved several media of a wide polarity range, solvent dependence of the absorption and fluorescence spectral shift were studied for the estimation of change of dipole moment on electronic excitation of the molecule.…”

Section: Introductionmentioning

confidence: 99%

Dual Fluorescence of Ellipticine: Excited State Proton Transfer from Solvent versus Solvent Mediated Intramolecular Proton Transfer

et al. 2011

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Photophysical properties of a natural plant alkaloid, ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole), which comprises both proton donating and accepting sites, have been studied in different solvents using steady state and time-resolved fluorescence techniques primarily to understand the origin of dual fluorescence that this molecule exhibits in some specific alcoholic solvents. Ground and excited state calculations based on density functional theory have also been carried out to help interpretation of the experimental data. It is shown that the long-wavelength emission of the molecule is dependent on the hydrogen bond donating ability of the solvent, and in methanol, this emission band arises solely from an excited state reaction. However, in ethylene glycol, both ground and excited state reactions contribute to the long wavelength emission. The time-resolved fluorescence data of the system in methanol and ethylene glycol indicates the presence of two different hydrogen bonded species of ellipticine of which only one participates in the excited state reaction. The rate constant of the excited state reaction in these solvents is estimated to be around 4.2-8.0 × 10(8) s(-1). It appears that the present results are better understood in terms of solvent-mediated excited state intramolecular proton transfer reaction from the pyrrole nitrogen to the pyridine nitrogen leading to the formation of the tautomeric form of the molecule rather than excited state proton transfer from the solvents leading to the formation of the protonated form of ellipticine.

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“…However, because of the short length of the oligonucleotide used by Jain and coworkers, it has been questioned whether that structure represents the real DNA-binding mode (Garbett & Graves, 2004). Also, molecular-dynamics simulations suggested an alternative binding mode for one of its most studied derivatives, 9-hydroxyellipticine (Elcock et al, 1996). According to these, 9-hydroxyellipticine would # 2005 International Union of Crystallography Printed in Denmark -all rights reserved…”

Section: Introductionmentioning

confidence: 99%

The anticancer agent ellipticine unwinds DNA by intercalative binding in an orientation parallel to base pairs

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et al. 2005

Acta Crystallogr D Biol Crystallogr

126

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Ellipticine is a natural plant product that has been found to be a powerful anticancer drug. Although still unclear, its mechanism of action is considered to be mainly based on DNA intercalation and/or the inhibition of topoisomerase II. Many experimental data suggest an intercalation based on stacking interactions along the major base‐pair axis, but alternative binding modes have been proposed, in particular for ellipticine derivatives. The 1.5 Å resolution structure of ellipticine complexed to a 6 bp oligonucleotide unveils its mode of binding and enables a detailed analysis of the distorting effects of the drug on the DNA.

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Theoretical studies of the intercalation of 9-hydroxyellipticine in DNA

Cited by 14 publications

References 53 publications

Sequence-Dependent Configurational Entropy Change of DNA upon Intercalation

Sequence-Dependent Configurational Entropy Change of DNA upon Intercalation

Dual Fluorescence of Ellipticine: Excited State Proton Transfer from Solvent versus Solvent Mediated Intramolecular Proton Transfer

The anticancer agent ellipticine unwinds DNA by intercalative binding in an orientation parallel to base pairs

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