Synthesis and antiproliferative activity of 2,7-diamino l0-(3,5-dimethoxy)benzyl-9(10H)-acridone derivatives as potent telomeric G-quadruplex DNA ligands

• A series of acridones with terminal ammonium substituents were synthesized.
• The in vitro cytotoxic effect in cancer cells were evaluated.
• 6a bearing dimethylamine substituents exhibited the highest cytotoxicity.
• 6a displayed little toxicity against normal 293T cells.
• The antitumor activity of 6a might be due to its stabilization of G-quadruplex DNA.

A novel series of l0-(3,5-dimethoxy)benzyl-9(10H)-acridone derivatives with terminal ammonium substituents at C2 and C7 positions on the acridone ring were successfully synthesized as antiproliferation agents. The biologic activity of the acridone compounds against leukemia CCRF-CEM cells demonstrated that some of the compounds displayed good antiproliferative activity, among which compound 6a containing dimethylamine substituents at the terminal C2 and C7 positions exhibited the highest cytotoxicity with IC50 at 0.3 μM. In addition compound 6a showed little toxicity against normal 293T cells proliferation with IC50 more than 100 μM. Further study indicated that compound 6a had strong binding activity to human telomeric G-quadruplex DNA, as detected by mass spectrometry, CD spectroscopy, UV absorption, FRET and fluorescence quenching assays. Our data suggested that the activity of 6a might be associated with its stabilization of G-quadruplex DNA, which can be developed as potent antitumor agent.

A novel series of l0-(3,5-dimethoxy)benzyl-9(10H)-acridone derivatives with terminal ammonium substituents at C2 and C7 positions on the acridone ring were successfully synthesized as potent telomeric G-quadruplex DNA ligands and antitumor agents.Figure optionsDownload as PowerPoint slide