Novel trisubstituted acridines as human telomeric quadruplex binding ligands

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biophysics

Background:

• BRACO19 is a known DNA G-quadruplex stabilizer.
• Telomeric G-quadruplexes are targets for cancer therapeutics.
• Acridine derivatives offer a scaffold for developing novel DNA-binding agents.

Purpose of the Study:

• To synthesize and characterize novel trisubstituted acridine derivatives.
• To evaluate their ability to stabilize human telomeric DNA G-quadruplexes.
• To assess their effect on cancer cell proliferation and toxicity.

Main Methods:

• Chemical synthesis of acridine derivatives.
• UV-vis spectroscopy, circular dichroism, linear dichroism, and viscosimetry for DNA binding studies.
• Cell cycle analysis and cytotoxicity assays.

Main Results:

• All synthesized acridine derivatives stabilized the human telomeric DNA G-quadruplex.
• Derivative 15 showed the highest stabilizing capability.
• Compounds induced S- and G2M-phase cell cycle arrest, with derivatives 13 and BRACO19 effectively suppressing proliferation.
• Derivatives exhibited lower toxicity to human fibroblasts than HT 29 cancer cells.

Conclusions:

• Novel acridine derivatives effectively mimic BRACO19's G-quadruplex stabilizing effects.
• These compounds represent promising candidates for anticancer drug development.
• Further investigation into their therapeutic potential is warranted.