Trisubstituted Acridines as G-quadruplex Telomere Targeting Agents.Effects of Extensions of the 3,6- and 9-Side Chains on Quadruplex Binding,Telomerase Activity,and Cell Proliferation

摘要

The synthesis is reported of a group of 3,6,9-trisubstituted acridine compounds as telomeric quadruplex-stabilizing ligands with systematic variations at the 3-,6-,and 9-positions.A new microwave-assisted methodology has been developed for trisubstituted acridine synthesis.Structure-activity relationships are reported using surface plasmon resonance and a fluorescence melting assay to examine quadruplex binding,together with a telomerase inhibition assay.These reveal relationships between G-quadruplex stabilization and telomerase inhibition and optimal 3,6- and 9-substituent side-chain lengths for maximal activity.Qualitative molecular modeling using molecular dynamics simulations has been undertaken on four quadruplex-DNA complexes.Long-term exposure of MCF7 cancer cells to a subset of the most active compounds,at doses lower than the IC_(50) values,showed that one compound produced a marked decrease in population growth,accompanied by senescence,which is consistent with telomere targeting by this agent.