title: Identification of novel RHPS4-derivative ligands with improved toxicological profiles and telomere-targeting activities.
abstract: 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.
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d'Oro 156, 00158, Rome, Italy. angela.rizzo@ifo.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Rizzo
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d'Oro 156, 00158, Rome, Italy. sara.iachettini@gmail.com.
authors.forename: Sara
authors.initials: S
authors.lastname: Iachettini
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d'Oro 156, 00158, Rome, Italy. zizza@ifo.it.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Zizza
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d'Oro 156, 00158, Rome, Italy. chiara.cingolani@hotmail.com.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cingolani
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d'Oro 156, 00158, Rome, Italy. manuelaporru@tiscali.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Porru
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d'Oro 156, 00158, Rome, Italy. artusem@inwind.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Artuso
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK. Malcolm.Stevens@nottingham.ac.uk.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Stevens
authors.affiliation: Pharminox Ltd, Biocity, Pennyfoot St, Nottingham, NG1 1GF, UK. marc.hummersone@pharminox.com.
authors.forename: Marc
authors.initials: M
authors.lastname: Hummersone
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d'Oro 156, 00158, Rome, Italy. biroccio@ifo.it.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d'Oro 156, 00158, Rome, Italy. erica.salvati@gmail.com.
authors.forename: Erica
authors.initials: E
authors.lastname: Salvati
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d'Oro 156, 00158, Rome, Italy. leonetti@ifo.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D008024:Ligands; D008564:Membrane Potentials; D015394:Molecular Structure; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D016615:Telomere / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; D000970:Antineoplastic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2