title: Synthesis, biophysical and biological evaluation of 3,6-bis-amidoacridines with extended 9-anilino substituents as potent G-quadruplex-binding telomerase inhibitors.
abstract: Telomerase and telomere maintenance are emerging targets for the treatment of human cancers. We report here on the targeting of the telomere-telomerase complex with a series of small molecules based on an acridine platform. A series of 3,6-bisamidoacridines with extended 9-anilino sidechains were designed and synthesised as potential telomeric G-quadruplex DNA (G4) interacting compounds. G4-stabilisation was assessed using a high-throughput FRET (fluorescence resonance energy transfer) assay and telomerase inhibition quantified by a modified TRAP (telomerase repeat amplification protocol) method. Within the series, the compounds showed significant G4-stabilising ability (Delta T(m) values of 25-36 degrees C at 1 microM concentration) and telomerase inhibition in the nanomolar region ((tel)EC(50) values of 80-318 nM). Furthermore, a direct correlation between the FRET and TRAP assays was observed, supporting the use of the rapid screening FRET assay for early assessment of potential G4-stabilising telomerase inhibitors.
authors.affiliation: Cancer Research UK Biomolecular Structure Group, University of London School of Pharmacy, 29/39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Schultes
authors.forename: Bérangère
authors.initials: B
authors.lastname: Guyen
authors.forename: Javier
authors.initials: J
authors.lastname: Cuesta
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000814:Aniline Compounds / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D031541:Fluorescence Resonance Energy Transfer; D011485:Protein Binding; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000166:Acridines; D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D019098:Telomerase; C023650:aniline