Refining our methodologies for assessing quadruplex DNA ligands; selectivity or an illusion of selectivity?

Oskouie, Akbar Amjadi; Abiri, Ardavan

doi:10.1016/j.ab.2020.113744

Cited by 3 publications

(2 citation statements)

References 46 publications

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“…Nonetheless, G4-disruptive small molecules have significant therapeutic potential, as highlighted recently by Monchaud et al, across diseases with their origins in helicase impairment, including in a number of genetic and neurological disorders . Design of small molecules that can both probe and disrupt G4 structures offers an elusive but desirable therapeutic prospect . Indeed, one of the most compelling ways to confirm the G4 presence in vivo is by direct visualization, e.g., through fluorescence imaging.…”

Section: Introductionmentioning

confidence: 99%

“… 38 Design of small molecules that can both probe and disrupt G4 structures offers an elusive but desirable therapeutic prospect. 39 Indeed, one of the most compelling ways to confirm the G4 presence in vivo is by direct visualization, e.g., through fluorescence imaging. The earliest imaging-based evidence for in cellulo G4 originated from fixed cell studies using labeled antibodies toward G4.…”

Section: Introductionmentioning

confidence: 99%

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Selective, Disruptive Luminescent Ru(II) Polypyridyl Probes of G-Quadruplex

et al. 2023

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Sensors capable of transducing G-quadruplex DNA binding are important both in solution and for imaging and interrogation in cellulo. Ru(II)-based light switches incorporating dipyridylphenazine (dppz) ligands are effective probes for recognition and imaging of DNA and its polymorphs including G-quadruplex, although selectivity is a limitation. While the majority of Ru(II)-based light switches reported to date, stabilize the quadruplex, imaging/theranostic probes that can disrupt G4s are of potentially enormous value in study and therapy for a range of disease states. We report here, on a Ru(II) complex (Ru-PDC3) that assembles the light switch capability of a Ru(II) dipyridylphenazine complex with the well-known G4-selective ligand Phen-DC3, into a single structure. The complex shows the anticipated light switch effect and strong affinity for G4 structures. Affinity depended on the G4 topology and sequence, but across all structures bar one, it was roughly an order of magnitude greater than for duplex or single-stranded DNA. Moreover, photophysical and Raman spectral data showed clear discrimination between duplex DNA and G4-bound structures offering the prospect of discrimination in imaging as well as in solution. Crucially, unlike the constituent components of the probe, Ru-PDC3 is a powerful G4 disrupter. From circular dichroism (CD), a reduction of ellipticity of the G4 between 70 and 95% was observed depending on topology and in many cases was accompanied by an induced CD signal for the metal complex. The extent of change in ellipticity is amongst the largest reported for small-molecule ligand G4 binding. While a promising G4 probe, without modification, the complex is fully water-soluble and readily permeable to live cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%