Rational Design of Acridine-Based Ligands with Selectivity for Human Telomeric Quadruplexes

S. Sparapani, Shozeb Haider, F. Doria, M. Gunaratnam, S. Neidle

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)12263-12272
Number of pages10
JournalJournal of the American Chemical Society
Volume132
Issue number35
DOIs
Publication statusPublished - 08 Aug 2010

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G-Quadruplexes
Acridines
DNA
Triazoles
Ligands
Lead compounds
Click Chemistry
Cells
Cell Line
Telomerase
Telomere
Molecular Structure
Freezing
Neoplasms
Hot Temperature
Molecular structure
Enzymes
Tumors
Melting
Thermodynamic stability

Cite this

Sparapani, S. ; Haider, Shozeb ; Doria, F. ; Gunaratnam, M. ; Neidle, S. / Rational Design of Acridine-Based Ligands with Selectivity for Human Telomeric Quadruplexes. In: Journal of the American Chemical Society. 2010 ; Vol. 132, No. 35. pp. 12263-12272.
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Rational Design of Acridine-Based Ligands with Selectivity for Human Telomeric Quadruplexes. / Sparapani, S.; Haider, Shozeb; Doria, F.; Gunaratnam, M.; Neidle, S.

In: Journal of the American Chemical Society, Vol. 132, No. 35, 08.08.2010, p. 12263-12272.

Research output: Contribution to journalArticle

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