Structural basis for stabilization of human telomeric G-quadruplex [d-(TTAGGGT)]₄ by anticancer drug epirubicin

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Anthracyclines are anticancer drugs with diverse mechanisms, including telomerase regulation and DNA synthesis inhibition.
• Telomerase plays a crucial role in cancer cell proliferation by maintaining telomere length.

Purpose of the Study:

• To investigate the binding interaction between epirubicin and G-quadruplex (G4) DNA.
• To elucidate the binding mode and its effect on G4 DNA stability and telomerase activity.

Main Methods:

• 1H and 31P Nuclear Magnetic Resonance (NMR) spectroscopy.
• Diffusion Ordered Spectroscopy (DOSY) and molecular dynamics simulations.
• Differential Scanning Calorimetry (DSC) and imino proton NMR for thermal stability.

Main Results:

• Epirubicin forms a well-defined complex with G4 DNA, confirmed by NMR chemical shift changes and line broadening.
• Binding is external, not intercalative, involving specific interactions near the T1-T2-A3 and G6pT7 sites.
• Epirubicin binding significantly stabilizes G4 DNA thermally, increasing its melting temperature by approximately 36°C.

Conclusions:

• Epirubicin interacts with G-quadruplex DNA through an external binding mode.
• The observed thermal stabilization of G4 DNA by epirubicin may impede telomerase association with telomeres.
• Findings suggest potential for developing novel anticancer drugs targeting G4 structures by modifying epirubicin's ring D or daunosamine sugar.