Nonintercalating DNA-binding ligands: Specificity of the interaction and their use as tools in biophysical, biochemical and biological investigations of the genetic material

Zimmer, Christoph; Wähnert, U.

doi:10.1016/0079-6107(86)90005-2

Cited by 766 publications

(412 citation statements)

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“…DNA can assume different conformations and can exhibit variable electrostatic binding free energy depending on the nature of solvent, temperature, pH, and ligands (Mathieson & Olayemi, 1975;Ott et al, 1975;Record, 1975;Wolf et al, 1975;Avitabile et al, 1980;Masotti et al, 1981;Wilson et al, 1985b;Misra et al, 1994). More interesting are the changes in local conformation that the DNA molecule can undergo upon interaction with proteins (Syvanen, 1975;Burckhardt et al, 1976a,b;Champoux, 1978) and other molecules in a cell (Pullman & Pullman 1981;Dervan, 1986;Zimmer & Waehnert, 1986). The study of DNA conformation and flexibility has been one of the major goals of the physicalchemistry investigation of DNA (Mohan & Yathindra, 1991;Eis & Millar, 1993;Kahn et al, 1994).…”

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confidence: 99%

Torsional Dynamics and Orientation of DNA−DAPI Complexes

Barcellona

Gratton

1996

Biochemistry

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The flexibility of calf thymus DNA and several polynucleotides was measured using the anisotropy decay of DAPI bound to DNA, a minor groove probe. DNA torsional dynamics were analyzed using the Schurr model [Allison, S. A., & Schurr, J. M. (1979) Chem. Phys. 41, 35-44] in the infinite polymer length approximation. Time-resolved fluorescence depolarization was measured using a frequencydoubled mode-locked dye laser and frequency-domain acquisition methods. At very high P/D ratios, the anisotropy decay is dominated by DNA torsional dynamics. The recovered values of the torsional elastic constant were in good agreement with literature values obtained using other DNA probes. The exact knowledge of the angle between the probe emission dipole transition moment and the helix axis is critical for the determination of the polymer elastic constant. At low P/D ratios, energy transfer between dye molecules strongly contributes to the anisotropy decay. We have developed a statistical model that describes the anisotropy decay, when the correct geometrical factors are included. At low P/D ratios the anisotropy decay is dominated by fluorescence homotransfer. In this regime, it is possible to determine the orientation of the dye molecule with respect to the polymer with accuracy. The values obtained for the distance and orientation of the DAPI molecules in solution using the fluorescence measurements are in excellent agreement with those from the crystal structure of the oligonucleotides-DAPI complex by Dickerson's group [Larsen T.

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confidence: 99%

Torsional Dynamics and Orientation of DNA−DAPI Complexes

Barcellona

Gratton

1996

Biochemistry

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“…In drugs such as netropsin and distamycin, the "thin edge" of the molecules (roughly the 3.4 Å thickness of an aromatic ring) appear to possess the appropriate crescent shape and dimensions to nicely insert into the helical narrow minor groove of the duplex (which varies from ca. 4-6 Å; 94,95). This fit of the natural crescent shape of the these drugs to the natural curvature of the DNA is probably at least partially responsible for their tight binding and sequence specificity (hence the preference for many of these drugs for the narrower minor groove in AT-rich regions of DNA).…”

Section: Resultsmentioning

confidence: 99%

Two-Dimensional¹H and³¹P NMR Spectra of a Decamer Oligodeoxyribonucleotide Duplex and a Quinoxaline ([MeCys³, MeCys⁷]TANDEM) Drug Duplex Complex

Powers

Olsen

Gorenstein

1989

Journal of Biomolecular Structure and Dynamics

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Assignment of the 1 H and 31 P NMR spectra of a decamer oligodeoxyribonucleotide duplex, d(CCCGATCGGG), and its quinoxaline ([MeCys 3 , MeCys 7 ]TANDEM) drug duplex complex has been made by two-dimensional 1 H-1 H and heteronuclear 31 P-1 H correlated spectroscopy. The 31 P chemical shifts of this 10 base pair oligonucleotide follow the general observation that the more internal the phosphate is located within the oligonucleotide sequence, the more upfield the 31 P resonance occurs. While the 31 P chemical shifts show sequence-specific variations, they also do not generally follow the Calladine "rules" previously demonstrated. 31 P NMR also provides a convenient monitor of the phosphate ester backbone conformational changes upon binding of the drug to the duplex. Although the quinoxaline drug, [MeCys 3 , MeCys 7 ]TANDEM, is generally expected to bind to duplex DNA by bis-intercalation, only small 31 P chemical shift changes are observed upon binding the drug to duplex d(CCCGATCGGG). Additionally, only small perturbations in the 1 H NMR and UV spectra are observed upon binding the drug to the decamer, although association of the drug stabilizes the duplex form relative to the other states. These results are consistent with a nonintercalative mode of association of the drug. Modeling and molecular mechanics energy minimization demonstrate that a novel structure in which the two quinoxaline rings of the drug binds in the minor groove of the duplex is possible.

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“…The precise mode of binding of these types of dicationic molcules with DNA has been found to be extremely sensitive to structure and dramatic differences in binding mode and specificity have resulted from relatively minor changes in structure [1][2][3][4]. The aromatic diamidines berenil and stilbamidine exhibit strong minor-groove binding at sites which have three or more consecutive AT base pairs [7,9]. However, the well-known DNA stain DAPI, 2-[4′-amidinophenyl]-6-amidinoindole, long known to bind in the minor groove of DNA at AT sites, has also been found to intercalate at GC sites [2].…”

Section: Introductionmentioning

confidence: 99%

Anti-Pneumocystis carinii pneumonia activity of dicationic 2,4-diarylpyrimidines

Kumar

Wilson

et al. 1996

European Journal of Medicinal Chemistry

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Summary-A synthesis of 2,4-bis-(4-amidinophenyl)pyrimidine 6, 2,4-bis-[(4-imidazolin-2-yl)phenyl)]pyrimidine 7, 2,4-bis[(4-tetrahydropyrimidinyl-2-yl)phenyl]pyrimidine 8, 2,4-bis Compounds 6, 9-11, and 20 given at 5 mg/kg are more active and less toxic than pentamidine at its effective dose when evaluated against Pneumocystis carinii pneumonia (PCP) in the immunosuppressed rat model. Several compounds in this series are being evaluated further as potential new anti-PCP agents.

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Nonintercalating DNA-binding ligands: Specificity of the interaction and their use as tools in biophysical, biochemical and biological investigations of the genetic material

Cited by 766 publications

References 264 publications

Torsional Dynamics and Orientation of DNA−DAPI Complexes

Torsional Dynamics and Orientation of DNA−DAPI Complexes

Two-Dimensional¹H and³¹P NMR Spectra of a Decamer Oligodeoxyribonucleotide Duplex and a Quinoxaline ([MeCys³, MeCys⁷]TANDEM) Drug Duplex Complex

Anti-Pneumocystis carinii pneumonia activity of dicationic 2,4-diarylpyrimidines

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Nonintercalating DNA-binding ligands: Specificity of the interaction and their use as tools in biophysical, biochemical and biological investigations of the genetic material

Cited by 766 publications

References 264 publications

Torsional Dynamics and Orientation of DNA−DAPI Complexes

Torsional Dynamics and Orientation of DNA−DAPI Complexes

Two-Dimensional1H and31P NMR Spectra of a Decamer Oligodeoxyribonucleotide Duplex and a Quinoxaline ([MeCys3, MeCys7]TANDEM) Drug Duplex Complex

Anti-Pneumocystis carinii pneumonia activity of dicationic 2,4-diarylpyrimidines

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Two-Dimensional¹H and³¹P NMR Spectra of a Decamer Oligodeoxyribonucleotide Duplex and a Quinoxaline ([MeCys³, MeCys⁷]TANDEM) Drug Duplex Complex