title: Evaluation of by disubstituted acridone derivatives as telomerase inhibitors: the importance of G-quadruplex binding.
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.
authors.affiliation: Cancer Research UK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: R John
authors.initials: RJ
authors.lastname: Harrison
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Reszka
authors.forename: Shozeb M
authors.initials: SM
authors.lastname: Haider
authors.forename: Barbara
authors.initials: B
authors.lastname: Romagnoli
authors.forename: James
authors.initials: J
authors.lastname: Morrell
authors.forename: Martin A
authors.initials: MA
authors.lastname: Read
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Gowan
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Incles
authors.forename: Lloyd R
authors.initials: LR
authors.lastname: Kelland
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D054831:Acridones; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors; D054856:G-Quadruplexes; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding / Q000502:physiology; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000166:Acridines; D054831:Acridones; D004791:Enzyme Inhibitors; C041300:acridone; D004247:DNA; D019098:Telomerase