Missailidis, Sotiris; Stanslas, Johnson; Modi, Chetna; Ellis, Michael J.; Robins, R Adrian; Laughton, Charles A. and Stevens, Malcolm F.G.
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The biophysical and biological characterization of 8,13-diethyl-6-methylquino[4,3,2-kl]acridinium iodide (6) is reported. The compound binds to DNA, as measured by UV, fluorescence, and circular dichroism studies, and stabilizes the double helix and higher order DNA structures (DNA triplexes and quadruplexes) against thermal denaturation. Unlike many DNA ligands, (6) shows no specificity for binding to specific base pair combinations and does not inhibit topoisomerase I (topo 1) or topo II activity. Furthermore, the biological fingerprint elicited by (6) in in vitro evaluations does not compare with clinical agents of the topo H inhibition class. The compound provokes cell cycle arrest in response to DNA damage and the biological sequelae are dependent on the p53 status of the cell line. DNA damage by (6) upregulates p53 and p2l(CIP/) WAR proteins. The unusual structure of (6) and its ease of synthesis in a "one-pot" reaction are features that are being exploited in the design and development of a new series of G-quadruplex stabilizing telomerase inhibitors. However, although the second-generation compounds that resulted from (6) present strong telomerase inhibition, (6) in itself presents yet a different mode of action, with a strong preference for triplex DNA, sequences often found in a number of genes.
|Item Type:||Journal Article|
|Keywords:||polycyclic acridine derivatives; DNA binding; spectrophotometric analysis; UV; fluorescence; circular dichroism; ligand-DNA systems; anti-tumor agents; anti-tumour agents; intercalating agents; ligand binding; telomerase inhibitors|
|Academic Unit/Department:||Science > Life, Health and Chemical Sciences|
|Interdisciplinary Research Centre:||Biomedical Research Network (BRN)|
|Depositing User:||Sotiris Missailidis|
|Date Deposited:||06 Jul 2006|
|Last Modified:||10 Mar 2014 10:31|
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