Abstract
Quadruplex (G4) forming sequences in telomeric DNA and c-myc promoter regions of human DNA are associated with tumorogenesis. Ligands that can facilitate or stabilize the formation and increase the stabilization of G4 can prevent tumor cell proliferation and have been regarded as potential anti-cancer drugs. In the present study, steady state and time-resolved fluorescence measurements provide important structural and dynamical insights into the free and bound states of the therapeutically potent plant flavonoid fisetin (3,3′,4′,7-tetrahydroxyflavone) in a G4 DNA matrix. The excited state intra-molecular proton transfer (ESPT) of fisetin plays an important role in observing and understanding the binding of fisetin with the G4 DNA. Differential absorption spectra, thermal melting, and circular dichroism spectroscopic studies provide evidences for the formation of G4 DNA and size exclusion chromatography (SEC) proves the binding and 1∶1 stoichiometry of fisetin in the DNA matrix. Comparative analysis of binding in the presence of EtBr proves that fisetin favors binding at the face of the G-quartet, mostly along the diagonal loop. Time resolved fluorescence anisotropy decay analysis indicates the increase in the restrictions in motion from the free to bound fisetin. We have also investigated the fingerprints of the binding of fisetin in the antiparallel quadruplex using Raman spectroscopy. Preliminary results indicate fisetin to be a prospective candidate as a G4 ligand.
Highlights
A little over a hundred years ago, in 1910, the German scientist I
The circular dichroism (CDs) spectrum probes the asymmetry of bases where at wavelengths .200 nm, the asymmetry arises as a result of stacking interactions of bases [23,24] and coupling with backbone transitions
In the presence of fisetin, there is no significant change in the CD spectral features of the DNA, indicating that, the base stacking of the G-quartet is conserved, highlighting the noninvasive nature of fisetin binding in quadruplex matrix
Summary
A little over a hundred years ago, in 1910, the German scientist I. G4 sequences are rich in the genome, human telomeric DNA and proto-oncogenes have the higher potential to form G4 DNA, compared to tumor-suppressor genes [10], suggesting the possibility of treating cancer cells distinctively with effective G4-ligands. This opens the door to small-molecule based ligand- telomeric G4 in cancer therapy. The purpose of this study is to examine the influence and stability of a medicinally potent drug fisetin in a quadruplex matrix in order to get a better insight into the factors regulating the formation and stabilization of the G4 structure. The information obtained is likely to be useful for the development of new G-quadruplex-based therapeutic agents
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