title: 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.
abstract: 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.
authors.affiliation: Cancer Research UK Biomolecular Structure Group, The School of Pharmacy, University of London, London WC1N 1AX, UK.
authors.forename: Michael J B
authors.initials: MJ
authors.lastname: Moore
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Schultes
authors.forename: Javier
authors.initials: J
authors.lastname: Cuesta
authors.forename: Francisco
authors.initials: F
authors.lastname: Cuenca
authors.forename: Mekala
authors.initials: M
authors.lastname: Gunaratnam
authors.forename: Farial A
authors.initials: FA
authors.lastname: Tanious
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D020349:Surface Plasmon Resonance; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D008024:Ligands; D004247:DNA; D019098:Telomerase