ABSTRACT
A series of tri- and tetra-substituted naphthalene diimides have been designed and synthesized. Several compounds show exceptional affinity for telomeric G-quadruplex DNA in classical and competition FRET assays and SPR studies. They inhibit telomerase in the TRAP assay, and show potent senescence-based short-term anti-proliferative effects on MCF7 and A549 cancer cell lines, and localize in the nucleus and particularly the nucleolus of MCF7 cells.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , G-Quadruplexes , Phenanthrolines/chemistry , Phenanthrolines/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Fluorescence Resonance Energy Transfer , Humans , Imides , Ligands , Models, Molecular , Molecular Structure , Naphthalenes , Phenanthrolines/pharmacology , Telomerase/antagonists & inhibitorsABSTRACT
The trisubstituted acridine compound BRACO-19 has been developed as a ligand for stabilising G-quadruplex structures. It is shown here that BRACO-19 produces short- and long-term growth arrest in cancer cell lines, and is significantly less potent in a normal cell line. BRACO-19 reduces telomerase activity and long-term telomere length attrition is observed. It is also shown that BRACO-19 binds to telomeric single-stranded overhang DNA, consistent with quadruplex formation, and the single-stranded protein hPOT1 has been shown to be displaced from the overhang in vitro and in cellular experiments. It is concluded that the cellular activity of BRACO-19 can be ascribed both to the uncapping of 3' telomere ends and to telomere shortening that may preferentially affect cells with short telomeres.
Subject(s)
Acridines/pharmacology , Antineoplastic Agents/pharmacology , Telomerase/antagonists & inhibitors , Telomere/metabolism , Acridines/chemistry , Antineoplastic Agents/chemistry , Cell Line , Dose-Response Relationship, Drug , Humans , Molecular StructureABSTRACT
The design, synthesis, biophysical and biochemical evaluation is presented of a new series of benzylamino-substituted acridines as G-quadruplex binding telomerase inhibitors. Replacement of the previously reported anilino substituents by benzylamino groups results in enhanced quadruplex interaction, and for one compound, superior telomerase inhibitory activity.