Evaluation of by disubstituted acridone derivatives as telomerase inhibitors: the importance of G-quadruplex binding

Bioorg Med Chem Lett. 2004 Dec 6;14(23):5845-9. doi: 10.1016/j.bmcl.2004.09.037.

Abstract

The synthesis and evaluation of a group of 2,6-, 2,7- and 3,6-bis-aminoalkylamido acridones are reported, which show a similar level of activity against telomerase in vitro compared to their acridine counterparts. Computer modelling and calculations of relative binding energies suggest an equivalent binding mode to human intramolecular G-quadruplex DNA, but with significantly reduced affinity, as a result of the limited delocalisation of the acridone chromophore compared to the acridine system. Thermal melting studies on acridone and acridine quadruplex complexes using a FRET approach support these predictions. Long-term cell proliferation studies at sub-cytotoxic doses with two representative acridones using the SKOV3 cell line, show that neither compound produces growth arrest, in contrast with the effects produced by the tri-substituted acridine compound BRACO-19. It is concluded that telomerase inhibitory activity is a necessary though by itself insufficient property in order for cellular growth arrest to occur at sub-toxic concentrations, and that tight quadruplex binding is also required.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acridines / chemistry*
  • Acridines / metabolism*
  • Acridines / pharmacology
  • Acridones
  • Cell Line, Tumor
  • DNA / metabolism*
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors
  • G-Quadruplexes
  • Humans
  • Models, Molecular
  • Protein Binding / physiology
  • Telomerase / antagonists & inhibitors*
  • Telomerase / metabolism*

Substances

  • Acridines
  • Acridones
  • Enzyme Inhibitors
  • acridone
  • DNA
  • Telomerase