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

ABSTRACT: 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 ß2 adrenergic receptor, and M1, M2 and M3 muscarinic receptors was obse

SUBMITTER: Iachettini S 

PROVIDER: S-EPMC3849007 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature