A wide range of therapies and imaging agents target biomolecules such as DNA and proteins. However, it is often difficult to design drugs and molecular probes with high selectivity for a given target whilst also controlling their cellular permeability and localisation. A biomolecule that has recently attracted significant interest is G-quadruplex DNA, a tetra-stranded nucleic acid structure which has been implicated in telomere maintenance, gene regulation and replication. Herein we report a new approach towards the controlled DNA binding properties and cellular uptake and localisation of a small molecule. More specifically, we report the synthesis of rotaxanes which incorporate as a stoppering unit a known G-quadruplex DNA binder, namely a Pt II-salphen complex. This compound is prevented from interacting with DNA when it is part of the mechanically interlocked assembly. The second rotaxane stopper was designed to be cleaved by either light or the activity of an esterase. In the presence of such stimuli, the rotaxane breaks apart, releasing the Pt II-salphen complex and activating its ability to bind to G-quadruplex DNA. Furthermore, we show that the rotaxanes regulate the cell uptake of this metal complex as well as its cytotoxicity. While the free G-quadruplex DNA binder is not cell permeable (and therefore not cytotoxic), when incorporated in the rotaxane it is readily taken up by cells. The cytotoxicity of the light-triggerable rotaxane in osteosarcoma U2OS cells increases dramatically after the incubated cells were exposed to light. Finally, we show that once the rotaxanes are broken apart inside the cell (either by light or esterases), a significant proportion of the freed G-quadruplex binder localises in the cell nucleus.

Guanine‐rich sequences of DNA are known to readily fold into tetra‐stranded helical structures known as G‐quadruplexes (G4). Due to their biological relevance, G4s are potential anticancer drug targets and therefore there is significant interest in molecules with high affinity for these structures. Most G4 binders are polyaromatic planar compounds which π–π stack on the G4′s guanine tetrad. However, many of these compounds are not very selective since they can also intercalate into duplex DNA. Herein we report a new class of binder based on an octahedral cobalt(III) complex that binds to G4 via a different mode involving hydrogen bonding, electrostatic interactions and π–π stacking. We show that this new compound binds selectivity to G4 over duplex DNA (particularly to the G‐rich sequence of the c‐myc promoter). This new octahedral complex also has the ability to template the formation of G4 DNA from the unfolded sequence. Finally, we show that upon binding to G4, the complex prevents helicase Pif1‐p from unfolding the c‐myc G4 structure.

The important role that G-quadurplex DNA (G4 DNA) structures play in regulating biological processes is becoming widely recognised. These structures have also been proposed to be attractive drug targets. Therefore,...

G-Quadruplex DNA structures have attracted increasing attention due to their biological roles and potential as targets for the development of new drugs. While most guanine-rich sequences in the genome have the potential to form monomeric G-quadruplexes, certain sequences have enough guanine-tracks to give rise to multimeric quadruplexes. One of these sequences is the human telomere where tandem repeats of TTAGGG can lead to the formation of two or more adjacent G-quadruplexes. Herein we report on the modular synthesis via click chemistry of dimeric metal-salphen complexes (with NiII and PtII) bridged by either polyether or peptide linkers. We show by circular dichroism (CD) spectroscopy that they generally have higher selectivity for dimeric vs monomeric G-quadruplexes. The emissive properties of the PtII-salphen dimeric complexes have been used to study their interactions with monomeric and dimeric G-quadruplexes in vitro as well as to study their cellular uptake and localization.

A wide range of therapies and imaging agents target biomolecules such as DNA and proteins. However, it is often difficult to design drugs and molecular probes with high selectivity for a given target whilst also controlling their cellular permeability and localisation. A biomolecule that has recently attracted significant interest is G-quadruplex DNA, a tetra-stranded nucleic acid structure which has been implicated in telomere maintenance, gene regulation and replication. Herein we report a new approach towards the controlled DNA binding properties and cellular uptake and localisation of a small molecule. More specifically, we report the synthesis of rotaxanes which incorporate as a stoppering unit a known G-quadruplex DNA binder, namely a Pt II-salphen complex. This compound is prevented from interacting with DNA when it is part of the mechanically interlocked assembly. The second rotaxane stopper was designed to be cleaved by either light or the activity of an esterase. In the presence of such stimuli, the rotaxane breaks apart, releasing the Pt II-salphen complex and activating its ability to bind to G-quadruplex DNA. Furthermore, we show that the rotaxanes regulate the cell uptake of this metal complex as well as its cytotoxicity. While the free G-quadruplex DNA binder is not cell permeable (and therefore not cytotoxic), when incorporated in the rotaxane it is readily taken up by cells. The cytotoxicity of the light-triggerable rotaxane in osteosarcoma U2OS cells increases dramatically after the incubated cells were exposed to light. Finally, we show that once the rotaxanes are broken apart inside the cell (either by light or esterases), a significant proportion of the freed G-quadruplex binder localises in the cell nucleus.