Trisubstituted acridine derivatives as potent and selective telomerase inhibitors.

Harrison, R.J., Cuesta, J., Chessari, G., Read, M.A., Basra, S.K., Reszka, A.P., Morrell, J., Gowan, S.M., Incles, C.M., Tanious, F.A., Wilson, W.D., Kelland, L.R. and Neidle, S. (2003) Trisubstituted acridine derivatives as potent and selective telomerase inhibitors. Journal of Medicinal Chemistry, 46 (21). pp. 4463-4476. 10.1021/jm0308693.

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DOI: 10.1021/jm0308693


The synthesis and evaluation for telomerase-inhibitory and quadruplex DNA binding properties of three related series of rationally designed trisubstituted acridine derivatives are described. These are substituted on the acridine ring at the 2,6,9; 2,7,9; and 3,6,9 positions. The ability of several of the most potent compounds to interact with and stabilize an intramolecular G-quadruplex DNA was evaluated by surface plasmon resonance methods, and affinities were found to correlate with potency in a telomerase assay. The interactions of a number of compounds with a parallel quadruplex DNA structure were simulated by molecular modeling methods. The calculated interaction energies were compared with telomerase activity and showed generally consistent correlations between quadruplex affinity and telomerase inhibition. These data support a model for the action of these compounds that involves the stabilization of intermediate quadruplex structures that inhibit the elongation of telomeric DNA by telomerase in tumor cells.

Item Type:Article
Additional Information:Full text available in print and electronically from the School of Pharmacy Library.
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Cancer Research UK Biomolecular Structure Group
ID Code:1729
Journal or Publication Title:Journal of Medicinal Chemistry
Deposited By:Library Staff
Deposited On:11 Aug 2010 10:12
Last Modified:09 Jun 2011 14:35

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