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

86 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

ASJC Scopus subject areas

  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry
  • Chemistry(all)

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