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Overview

The pentacyclic acridinium salt RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl] acridinium methosulfate, compound 1) is one of the most interesting DNA G-quadruplex binding molecules due to its high efficacy in tumor cell growth inhibition both in in vitro models and in vivo against human tumor xenografts in combination with conventional chemotherapeutics. Despite compound 1 having desirable chemical and pharmaceutical properties, its potential as a therapeutic agent is compromised by off-target effects on cardiovascular physiology. In this paper we report a new series of structurally-related compounds which were developed in an attempt to minimize its off-target profile, but maintaining the same favorable chemical and pharmacological features of the lead compound. By performing a comparative analysis it was possible to identify which derivatives had the following properties: (i) to show a reduced capacity in respect to compound 1 to inhibit the hERG tail current tested in a patch clamp assay and/or to interact with the human recombinant β2 receptor; (ii) to maintain both a good G4-binding affinity and cancer cell selectivity; and (iii) to trigger DNA damage with specific telomere uncapping. These studies allowed us to identify a novel G4-stabilizing molecule, compound 8, being characterized by reduced off-target effects and potent telomere on-target properties compared to the prototypic compound 1. Moreover, compound 8 shares with compound 1 the same molecular mode of action and an anti-tumour activity specifically restricted to replicating cells, as evident with its particularly efficient activity in combination therapy with a topoisomerase I inhibitor. In conclusion, we have identified a new pentacyclic derivative 8 having suitable properties to be the focus of further investigations as a clinical candidate for cancer therapy.

10 Dec 2009·Molecular Cancer Therapeutics

Abstract C171: On- and off-target effects of telomere uncapping G-quadruplex ligands based on pentacyclic acridinium salts

Author: McCarroll, Andrew J. ; Hummersone, Marc ; Hutchinson, Ian ; Williams, Huw EL ; Stevens, Malcolm FG

AbstractAntitumor properties of the potent G-quadruplex ligand 3,11-difluoro-6,8, 13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) are driven by telomere uncapping events. RHPS4 has good selectivity for quadruplex DNA over duplex DNA as measured by surface plasmon resonance (Kquad 1.1 × 107 M−1); Kdup 3.4 × 105 M−1). In preclinical models of solid tumor xenografts RHPS4 potentiates the activity of camptothecins but good response is dependent on the timing of the drug sequence employed. These experiments teach how an agent of this novel class might be used clinically in combination with chemotherapeutic agents. Although RHPS4 has several ‘drug-like’ qualities (synthetic accessibility, water solubility, cellular uptake), a preliminary toxicological study revealed that the compound is a potent hERG inhibitor (IC50 0.2 M) and has additional receptor interactions, notably with muscarinic M1, M2 and M3 receptors. In an anaesthetized guinea pig cardiac model RHPS4 increased QTcB interval at doses of 5 and 10 mg/kg. Modifications to the peripheral substituents around the pentacyclic core have identified agents with differing on- and off-target effects. Removal of the N(13)-methyl group of RHPS4 to generate an uncharged molecule drastically reduced affinity for the target quadruplex DNA coupled with reduced pharmacological liabilities; increasing the size of the onium group at N(13) from Me to Et reduced affinity for quadruplex DNA (Kquad 0.6 × 106 M−1) and increased hERG inhibition (IC50 0.04 M). After a significant redesign program two isomeric compounds have been identified, 2- and 3-acetylamino-8,13-dimethyl-8H-quino[4,3,2-kl]acridinium iodides with ‘win-win’ profiles - better selectivity for quadruplex DNA and markedly reduced hERG liability (for the 2-acetylamino compound Kquad 2.4 × 107 M−1; Kdup 3.8 × 105 M−1; hERG IC50 3.7 M): for the 3-acetylamino isomer Kquad 2.5 × 107 M−1; Kdup 4.4 × 105 M−1; hERG IC50 18 M). Molecular modeling studies on the favored 3-acetylamino derivative indicate that the pentacyclic core acts as a surrogate K+ stabilizing the G-quadruplex structure with the acetylamino side-chain projecting into a quadruplex groove.Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C171.

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