Correlation of frameshift mutagenicity with dna intercalation by CGS 20928A using an in vitro DNA unwinding assay

Mattes, William B.; Kapeghian, John C.; Lasinski, E. R.; O'Lone, Susan D.; Puri, Emilio C.; Matheson, Dale W.

doi:10.1002/em.2850220108

Cited by 9 publications

(3 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As expected, only TB11, which displays a second binding site in the present work, retarded the migration of the pBR322 plasmid in the gel electrophoretic retardation experiments (Fig. ), a property that is attributable to drugs that intercalate into DNA base pairs .…”

Section: Resultssupporting

confidence: 87%

A targeted DNA substrate mechanism for the inhibition of HIV‐1 integrase by inhibitors with antiretroviral activity

et al. 2016

View full text Add to dashboard Cite

We recently reported that viral DNA could be the primary target of raltegravir ( RAL ), an efficient anti‐ HIV ‐1 drug, which acts by inhibiting integrase. To elucidate this mechanism, we conducted a comparative analysis of RAL and TB 11, a diketoacid abandoned as an anti‐ HIV ‐1 drug for its weak efficiency and marked toxicity, and tested the effects of the catalytic cofactor Mg 2+ (5 m m ) on drug‐binding properties. We used circular dichroism and fluorescence to determine drug affinities for viral DNA long terminal repeats ( LTR s) and peptides derived from the integrase active site and DNA retardation assays to assess drug intercalation into DNA base pairs. We found that RAL bound more tightly to LTR ends than did TB 11 (a diketo acid bearing an azido group) and that Mg 2+ significantly increased the affinity of both RAL and TB 11. We also observed a good relationship between drug binding with processed LTR and strand transfer inhibition. This unusual type of inhibition was caused by Mg 2+ ‐assisted binding of drugs to DNA substrate, rather than to enzyme. Notably, while RAL bound exclusively to the cleavable/cleaved site, TB 11 further intercalated into DNA base pairs and interacted with the integrase‐derived peptides. These unwanted binding sites explain the weaker bioavailability and higher toxicity of TB 11 compared with the more effective RAL .

show abstract

Section: Resultssupporting

confidence: 87%

A targeted DNA substrate mechanism for the inhibition of HIV‐1 integrase by inhibitors with antiretroviral activity

et al. 2016

View full text Add to dashboard Cite

show abstract

“…9-Acridinamine (the name generally used for the compound), one of the simplest representatives of the family of nitrogen organic bases, is a molecule interesting from the cognitive point of view owing to its relatively simple constitution and interesting physicochemical features, which are reflected, among other things, in its ability to interact with biomolecules. , For these reasons, 9-acridinamine has often been used as a model compound in studying the general properties of chemical entities. − Its biological relevance is exhibited by its mutagenic activity, − as well as its ability to interact with DNA ,− and other biologically important molecules. ,− Of some interest is the photodynamic activity of the compound. − 9-Acridinamine is also a convenient fluorescent probe for investigating pH and various physical features of biological systems. − …”

Section: Introductionmentioning

confidence: 99%

Hartree−Fock and Density Functional Methods and IR and NMR Spectroscopies in the Examination of Tautomerism and Features of Neutral 9-Acridinamine in Gaseous and Condensed Media

et al. 1997

View full text Add to dashboard Cite

Two tautomeric molecules, 9-acridinamine (9-AA) and 9(10H)-acridinimine (9-AI), were examined at the ab initio Hartree−Fock (HF) and density functional (DFT) levels of theory with the 6-31G** basis sets. Solvent (hexane, CH3CN, H2O) effects were included in ab initio HF optimizations through the self-consistent reaction field (SCRF) technique. Subsequent Hessian calculations followed by the normal-mode analyses revealed all harmonic frequencies to be positive, thus confirming the validity of the geometry optimizations. The energies of the molecules at stationary points corresponding to ab initio HF geometries were supplemented with the second-order Møller−Plesset (MP2) electron correlation correction. Standard routines utilizing relationships of statistical thermodynamics enabled determination of enthalpies of formation (supplemented further with corrections arising from isogyric, hydrogenation, and isodesmic processes) and entropies (heat capacities) at selected temperatures, as well as constants revealing equilibrium between two tautomeric forms. Other physicochemical characteristics, such as bond orders, dipole moments, and energies of the lowest unoccupied (LUMO) and highest occupied (HOMO) molecular orbitals were also obtained from theoretical calculations. Thermochemical data indicate that 9-AA and 9-AI should coexist at ambient temperature. This is also confirmed by a comparison of experimental IR and Raman spectra with harmonic frequencies derived theoretically. 1H and 13C chemical shifts obtained at the GIAO level of theory correlate only qualitatively with relevant experimental NMR data and do not exclude the existence of tautomeric phenomena. The distributions of atomic partial charges and electrostatic potential around the molecules differ noticeably, which implies that 9-AA and 9-AI may behave differently with respect to biomolecules.

show abstract

“…[13][14][15] The most spectacular property, however, is undoubtedly the anticancer activity of 9-AA derivatives, 16 -18 which is probably related to the intercalating ability of 9-AA itself. [19][20][21][22][23][24][25] Because the biological features of a compound are strongly connected to its structural characteristics, its propensity to exist in several tautomeric forms may account for the presence or lack of biological activity. It has been shown, for instance, that nitracrine ͑a 9-AA derivative͒ exhibiting anticancer activity 26 crystallizes in its imino form, 27,28 whereas its 2-nitro isomer, lacking antitumor properties, exists, in the solid phase, as a planar amino tautomer.…”

Section: Introductionmentioning

confidence: 99%

Is 9-acridinamine anion a dispersion-bound anion?

Skurski

Rak

Simons

2001

The Journal of Chemical Physics

View full text Add to dashboard Cite

The possibility of electron binding to 9-acridinamine ͑9-AA͒ was studied at the second order Møller-Plesset perturbation theory level with the aug-cc-pVDZ basis set augmented with a diffuse 6s6p4d set that has proven appropriate in earlier studies of weakly bound anions. It was found that both the amino and imino tautomers of 9-AA bind an excess electron to form stable anions. The vertical electron attachment energies corresponding to the amino and imino form were calculated to be 20 and 41 cm Ϫ1 , respectively. It was found that while the imino 9-AA tautomer forms a typical dipole-bound anion, the electron binding energy for the amino tautomer calculated at the electrostatic Koopmans' theorem level appears to be cancelled when the correlation correction to the dipole moment of the neutral is taken into account at the MP2 level. Therefore, the stability of the latter anion may be caused only by additional electron correlation effects, which are dominated by dispersion interactions. For this reason, we suggest that this anion may be termed a dispersion-bound anion.

show abstract

Correlation of frameshift mutagenicity with dna intercalation by CGS 20928A using an in vitro DNA unwinding assay

Cited by 9 publications

References 24 publications

A targeted DNA substrate mechanism for the inhibition of HIV‐1 integrase by inhibitors with antiretroviral activity

A targeted DNA substrate mechanism for the inhibition of HIV‐1 integrase by inhibitors with antiretroviral activity

Hartree−Fock and Density Functional Methods and IR and NMR Spectroscopies in the Examination of Tautomerism and Features of Neutral 9-Acridinamine in Gaseous and Condensed Media

Is 9-acridinamine anion a dispersion-bound anion?

Contact Info

Product

Resources

About