Antitumor polycyclic acridines. 20. Search for DNA quadruplex binding selectivity in a series of 8,13-dimethylquino[4,3,2-kl]acridinium salts: telomere-targeted agents
| Autor: | Mai-Kim Cheng, Andrew J. McCarroll, Sotiris Missailidis, Ian Hutchinson, Charles A. Laughton, Jean-Louis Mergny, Jennifer C. Cookson, W. David Wilson, M. F. G. Stevens, Chetna Modi, Farial A. Tanious, Robert A. Heald |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
DNA polymerase
Fluorescence spectrometry Antineoplastic Agents Heterocyclic Compounds 4 or More Rings chemistry.chemical_compound Structure-Activity Relationship Cell Line Tumor Drug Discovery Fluorescence Resonance Energy Transfer Humans heterocyclic compounds Surface plasmon resonance Telomerase Binding selectivity Cell Proliferation biology Nucleic acid sequence DNA Surface Plasmon Resonance Telomere G-Quadruplexes Quaternary Ammonium Compounds Förster resonance energy transfer chemistry Biochemistry biology.protein Molecular Medicine Acridines Growth inhibition Drug Screening Assays Antitumor |
| Zdroj: | Journal of medicinal chemistry. 51(4) |
| ISSN: | 0022-2623 |
| Popis: | The growth-inhibitory activities of an extensive series of quaternized quino[4,3,2- kl]acridinium salts against tumor cell lines in vitro have been measured and their biological properties interpreted in the light of differential binding to different DNA isoforms. Selectivity for quadruplex DNA binding and stabilization by compounds were explored through an array of methods: UV absorption and fluorescence emission spectroscopy, surface plasmon resonance, and competition dialysis. Quadruplex DNA interaction was further characterized through FRET and DNA polymerase arrest assays. Telomerase inhibition, inferred from the TRAP assay, is attributed to quadruplex stabilization, supported by the strong correlation (R(2) = 0.81) across the series between quadruplex DNA binding affinity and TRAP inhibition potency. Growth inhibition potency in the NCI60 human tumor cell line panel is more marked in compounds with greater DNA duplex binding affinity (R(2) = 0.82). Quantification of relative quadruplex and duplex binding affinity constants puts some of these ligands among the most selective quadruplex DNA interactive agents reported to date. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|