Rational design of acridine-based ligands with selectivity for human telomeric quadruplexes.

Sparapani, S., Haider, S.M., Doria, F., Gunaratnam, M. and Neidle, S. (2010) Rational design of acridine-based ligands with selectivity for human telomeric quadruplexes. Journal of the American Chemical Society, 132 (35). pp. 12263-12272. 10.1021/ja1003944.

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DOI: 10.1021/ja1003944


Structure-based modeling methods have been used to design a series of disubstituted triazole-linked acridine compounds with selectivity for human telomeric quadruplex DNAs. A focused library of these compounds was prepared using click chemistry and the selectivity concept was validated against two promoter quadruplexes from the c-kit gene with known molecular structures, as well as with duplex DNA using a FRET-based melting method. Lead compounds were found to have reduced effects on the thermal stability of the c-kit quadruplexes and duplex DNA structures. These effects were further explored with a series of competition experiments, which confirmed that binding to duplex DNA is very low even at high duplex:telomeric quadruplex ratios. Selectivity to the c-kit quadruplexes is more complex, with some evidence of their stabilization at increasing excess over human telomeric quadruplex DNA. Selectivity is a result of the dimensions of the triazole-acridine compounds, and in particular the separation of the two alkyl-amino terminal groups. Both lead compounds also have selective inhibitory effects on the proliferation of cancer cell lines compared to a normal cell line, and one has been shown to inhibit the activity of the telomerase enzyme, which is selectively expressed in tumor cells, where it plays a role in maintaining telomere integrity and cellular immortalization.

Item Type:Article
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Cancer Research UK Biomolecular Structure Group
ID Code:1785
Journal or Publication Title:Journal of the American Chemical Society
Deposited By:Library Staff
Deposited On:18 Feb 2011 16:28
Last Modified:11 Nov 2011 12:54

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