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 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.
Highlights
Telomeric DNA is protected and maintained at the ends of chromosomes by the action of the enzyme telomerase
We have shown previously by NMR studies that the agent stacks above and below the G3 core of a (TTAGGGT)4 parallelstranded quadruplex; [11] it binds with high efficiency to the h-Tel DNA sequence as measured by surface plasmon resonance [11], circular dichroism and ESI-MS [12,13]; it is an active inhibitor of telomerase (IC50 0.33 μM) as revealed in a Trap assay [14] and disrupts the shelterin complex of the telomere with the liberation of the POT-1 protein [15]
Fluorescence in situ hybridization (FISH) For metaphase chromosome preparation cells were treated with demecolcine (Sigma, Milan, Italy) 0.1 mg/ml for 4 h and harvested and washed in 75 mM KCl for 5 min at 37°C
Summary
Telomeric DNA is protected and maintained at the ends of chromosomes by the action of the enzyme telomerase. In this paper we report that the prototypic quinoacridinium salt 1 exhibits some undesirable off-target effects, but that these effects can be ameliorated to some extent in related non-fluorinated compounds 2 and 3 without compromising on-target properties. These physico-chemical and pharmacological studies offer hope that a suitable clinical candidate might yet emerge based on this pentacyclic chemotype
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
