Anticancer activity expressed by a library of 2,9-diazaperopyrenium dications

Karel J. Hartlieb, Leah S. Witus, Daniel P. Ferris, Ashish N. Basuray, Mohammed M. Algaradah, Amy A. Sarjeant, Charlotte L. Stern, Majed S. Nassar, Youssry Y. Botros, J. Fraser Stoddart*

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Polyaromatic compounds are well-known to intercalate DNA. Numerous anticancer chemotherapeutics have been developed upon the basis of this recognition motif. The compounds have been designed such that they interfere with the role of the topoisomerases, which control the topology of DNA during the cell-division cycle. Although many promising chemotherapeutics have been developed upon the basis of polyaromatic DNA intercalating systems, these candidates did not proceed past clinical trials on account of their dose-limiting toxicity. Herein, we discuss an alternative, water-soluble class of polyaromatic compounds, the 2,9-diazaperopyrenium dications, and report in vitro cell studies for a library of these dications. These investigations reveal that a number of 2,9-diazaperopyrenium dications show similar activities as doxorubicin toward a variety of cancer cell lines. Additionally, we report the solid-state structures of these dications, and we relate their tendency to aggregate in solution to their toxicity profiles. The addition of bulky substituents to these polyaromatic dications decreases their tendency to aggregate in solution. The derivative substituted with 2,6-diisopropylphenyl groups proved to be the most cytotoxic against the majority of the cell lines tested. In the solid state, the 2,6-diisopropylphenyl-functionalized derivative does not undergo π⋯π stacking, while in aqueous solution, dynamic light scattering reveals that this derivative forms very small (50-100 nm) aggregates, in contrast with the larger ones formed by dications with less bulky substituents. Alteration of the aromaticitiy in the terminal heterocycles of selected dications reveals a drastic change in the toxicity of these polyaromatic species toward specific cell lines.

Original languageEnglish (US)
Pages (from-to)1461-1470
Number of pages10
JournalACS nano
Volume9
Issue number2
DOIs
StatePublished - Feb 24 2015

Keywords

  • DNA intercalation
  • anticancer activity
  • diazaperopyrenium dications

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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  • Cite this

    Hartlieb, K. J., Witus, L. S., Ferris, D. P., Basuray, A. N., Algaradah, M. M., Sarjeant, A. A., Stern, C. L., Nassar, M. S., Botros, Y. Y., & Stoddart, J. F. (2015). Anticancer activity expressed by a library of 2,9-diazaperopyrenium dications. ACS nano, 9(2), 1461-1470. https://doi.org/10.1021/nn505895j