On and off-target effects of telomere uncapping G-quadruplex selective ligands based on pentacyclic acridinium salts

Sara Iachettini, Malcolm F.G. Stevens, Mark Frigerio, Marc G. Hummersone, Ian Hutchinson, Thomas P. Garner, Mark S. Searle, David W. Wilson, Manoj Munde, Rupesh Nanjunda, Carmen D'Angelo, Pasquale Zizza, Angela Rizzo, Chiara Cingolani, Federica De Cicco, Manuela Porru, Maurizio D'Incalci, Carlo Leonetti, Annamaria Biroccio, Erica Salvati

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Quadruplexes DNA are present in telomeric DNA as well as in several cancer-related gene promoters and hence affect gene expression and subsequent biological processes. The conformations of G4 provide selective recognition sites for small molecules and thus these structures have become important drug-design targets for cancer treatment. The DNA G-quadruplex binding pentacyclic acridinium salt RHPS4 (1) has many pharmacological attributes of an ideal telomere-targeting agent but has undesirable off-target liabilities. Notably a cardiovascular effect was evident in a guinea pig model, manifested by a marked and sustained increase in QTcB interval. In accordance with this, significant interaction with the human recombinant β2 adrenergic receptor, and M1, M2 and M3 muscarinic receptors was observed, together with a high inhibition of the hERG tail current tested in a patch clamp assay. Two related pentacyclic structures, the acetylamines (2) and (3), both show a modest interaction with β2 adrenergic receptor, and do not significatively inhibit the hERG tail current while demonstrating potent telomere on-target properties comparing closely with 1. Of the two isomers, the 2-acetyl-aminopentacycle (2) more closely mimics the overall biological profile of 1 and this information will be used to guide further synthetic efforts to identify novel variants of this chemotype, to maximize on-target and minimize off-target activities. Consequently, the improvement of toxicological profile of these compounds could therefore lead to the obtainment of suitable molecules for clinical development offering new pharmacological strategies in cancer treatment.

Original languageEnglish (US)
Article number68
JournalJournal of Experimental and Clinical Cancer Research
Issue number1
StatePublished - 2013
Externally publishedYes


  • Anti-cancer therapy
  • G-quadruplex
  • Telomere targeting agents

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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