Abstract
Guanine-rich DNA can form four-stranded structures called G-quadruplexes (G4s) that can regulate many biological processes. Metal complexes have shown high affinity and selectivity toward the quadruplex structure. Here, we report the comparison of a panel of platinum (II) complexes for quadruplex DNA selective recognition by exploring the aromatic core around terpyridine derivatives. Their affinity and selectivity towards G4 structures of various topologies have been evaluated by FRET-melting (Fluorescence Resonance Energy Transfert-melting) and Fluorescent Intercalator Displacement (FID) assays, the latter performed by using three different fluorescent probes (Thiazole Orange (TO), TO-PRO-3, and PhenDV). Their ability to bind covalently to the c-myc G4 structure in vitro and their cytotoxicity potential in two ovarian cancerous cell lines were established. Our results show that the aromatic surface of the metallic ligands governs, in vitro, their affinity, their selectivity for the G4 over the duplex structures, and platination efficiency. However, the structural modifications do not allow significant discrimination among the different G4 topologies. Moreover, all compounds were tested on ovarian cancer cell lines and normal cell lines and were all able to overcome cisplatin resistance highlighting their interest as new anticancer drugs.
Highlights
Among the clinically relevant anticancer drugs, cisplatin is the most frequently used chemotherapeutic drug employed for the treatment of testicular, ovarian, lung, head, and neck cancers
We explored the chemical space around the terpyridine aromatic core to put in evidence the key elements that drive affinity and selectivity for various G4-DNA exhibiting polymorphic (22AG), antiparallel (21CTA), long looped parallel (CEB25-WT), and short looped parallel (c-myc) topologies
The FRET-melting assays pointed out three ligands exhibiting higher binding inducing stabilization independently from the G4 topology (Figure 1A), namely Pt-BisQ, Pt-ctpy, and Pt-ttpy (∆Tm > 10 ◦ C)
Summary
Among the clinically relevant anticancer drugs, cisplatin is the most frequently used chemotherapeutic drug employed for the treatment of testicular, ovarian, lung, head, and neck cancers. One of the considered strategies is to induce different DNA lesions and to target specific DNA structures as G-quadruplexes (G4) [4]. G4 consists in the stacking of G-quartets formed by four guanines linked together by reverse-Hoogsteen hydrogen bonds involving their N7. G4s arise from DNA (or RNA) sequences that contain at least four runs of guanines and are stabilized by physiological concentrations of alkali metal cations. A large amount of data provides evidence that such structures could form in cells and may play important roles in biology, such as genomic
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