Selectivity of small molecule ligands for parallel and anti-parallel DNA G-quadruplex structures

Thomas P. Garner, Huw E.L. Williams, Katarzyna I. Gluszyk, Stephen Roe, Neil J. Oldham, Malcolm F.G. Stevens, John E. Moses, Mark S. Searle

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Abstract

We report CD, ESI-MS and molecular modelling studies of ligand binding interactions with DNA quadruplex structures derived from the human telomeric repeat sequence (h-Tel) and the proto-oncogenic c-kit promoter sequence. These sequences form anti-parallel (both 2 + 2 and 3 + 1) and parallel conformations, respectively, and demonstrate distinctively different degrees of structural plasticity in binding ligands. With h-Tel, we show that an extended heteroaromatic 1,4-triazole (TRZ), designed to exploit π-stacking interactions and groove-specific contacts, shows some selectivity for parallel folds, however, the polycyclic fluorinated acridinium cation (RHPS4), which is a similarly potent telomerase inhibitor, shows selectivity for anti-parallel conformations implicating favourable interactions with lateral and diagonal loops. In contrast, the unique c-kit parallel-stranded quadruplex shows none of the structural plasticity of h-Tel with either ligand. We show by quantitative ESI-MS analysis that both sequences are able to bind a ligand on either end of the quadruplex. In the case of h-Tel the two sites have similar affinities, however, in the case of the c-kit quadruplex the affinities of the two sites are different and ligand-dependent. We demonstrate that two different small molecule architectures result in significant differences in selectivity for parallel and anti-parallel quadruplex structures that may guide quadruplex targeted drug-design.

Original languageEnglish (US)
Pages (from-to)4194-4200
Number of pages7
JournalOrganic and Biomolecular Chemistry
Volume7
Issue number20
DOIs
Publication statusPublished - Oct 15 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Garner, T. P., Williams, H. E. L., Gluszyk, K. I., Roe, S., Oldham, N. J., Stevens, M. F. G., ... Searle, M. S. (2009). Selectivity of small molecule ligands for parallel and anti-parallel DNA G-quadruplex structures. Organic and Biomolecular Chemistry, 7(20), 4194-4200. https://doi.org/10.1039/b910505k