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

Journal of Experimental & Clinical Cancer Research

Erica Salvati⁴  Annamaria Biroccio⁴  Carlo Leonetti⁴  Maurizio D’Incalci⁵  Manuela Porru⁴  Federica De Cicco⁴  Chiara Cingolani⁴  Angela Rizzo⁴  Pasquale Zizza⁴  Carmen D’Angelo⁴  Rupesh Nanjunda⁶  Manoj Munde⁶  David W Wilson⁶  Mark S Searle¹  Thomas P Garner¹  Ian Hutchinson²  Marc G Hummersone²  Mark Frigerio²  Malcolm FG Stevens³  Sara Iachettini⁴ 

[1] Center for Biomolecular Sciences, School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK;Pharminox Ltd, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK;School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK;Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Via delle Messi D’Oro, 156 00158 Rome, Italy;Department of Oncology, Pharmacological Research Institute ‘Mario Negri’, Milan, Italy;Department of Chemistry, Georgia State University, P.O. Box 4098, Atlanta, Georgia 30302-4098

关键词: Anti-cancer therapy;    G-quadruplex;    Telomere targeting agents;   

Others  :  815123
DOI  :  10.1186/1756-9966-32-68

 received in 2013-07-26, accepted in 2013-08-29,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Iachettini et al.; licensee BioMed Central Ltd.

【 图 表 】

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