A Light‐up Logic Platform for Selective Recognition of Parallel G‐Quadruplex Structures via Disaggregation‐Induced Emission

Abstract

The design of turn‐on dyes with optical signals sensitive to the formation of supramolecular structures provides fascinating and underexplored opportunities for G‐quadruplex (G4) DNA detection and characterization. Here, we show a new switching mechanism that relies on the recognition‐driven disaggregation (on‐signal) of an ultrabright coumarin‐quinazoline conjugate. The synthesized probe selectively lights‐up parallel G4 DNA structures via the disassembly of its supramolecular state, demonstrating outputs that are easily integrable into a label‐free molecular logic system. Finally, our molecule preferentially stains the G4‐rich nucleoli of cancer cells.

A Minimalistic Coumarin Turn-On Probe for Selective Recognition of Parallel G-Quadruplex DNA Structures

“… The structures of the coumarin analogues reported by us in previous studies 35 , 47 and the structures of the three derivatives used in the present study ( 2a - c ). The coumarin scaffold is marked in red.…”

“… 3 Therefore, achieving selectivity between different G4 topologies still remains one of the most challenging tasks in this field. Some selective compounds have been recently reported such as a coumarin–quinazolinone, 35 a quinazoline–quinazolinone, 36 a core-extended naphthalene diimide, 37 squaraine dyes, 38 , 39 a thiazole peptide, 31 and anthracene-based, 40 BODIPY-based, 41 triarylimidazole-based, 42 and bis(quinolinium) pyridodicarboxamide-based 43 compounds. However, because of multiple mechanisms of action, chemical scaffolds that fall far outside the “druglike” chemical space, high molecular weights, the induction of conformational changes, and complicated multistep synthetic procedures further strategies are required to rationally design G4-interacting small optical probes as easily accessible diagnostic tools.…”

“…In previous studies, the coumarin scaffolds were usually extensively modified through the insertion of π-extended heterocyclic aromatic motifs in order to tune both the photophysical properties and G4-binding properties to both DNA and RNA ( Scheme 1 ). 19 , 35 , 43 − 47 Even if all these molecular recognition strategies have been successfully implemented in in vitro models and, in some cases, in fixed and live cells, the molecular sizes of some of these newly generated probes are not ideal for membrane permeability and might therefore hinder the detection of G4 DNA in live cells.…”

“…The most-selective G4 probes show high signal in the G4-rich nucleoli, 15 , 19 , 20 , 35 , 36 which are highly dense multifunctional domains in which ribosome biogenesis occurs with a high level of transcriptional activity involving both G4 DNA and RNA structures. 20 …”

“…Inspired by our recently published results on the use of coumarin–quinazolinone, 35 coumarin–benzothiazole, 47 and quinazoline–quinazolinone 15 , 36 compounds, we synthesized three low-molecular-weight amidinocoumarin derivatives with druglike characteristics that differed only by the nature of their electron-donating substituents that determine their fluorescence properties ( Scheme 1 ). By testing different G4 oligonucleotides, we found that two of these probes exhibited topology-specific G4-binding properties, but only one of them showed promising potential to detect G4 DNA in cells.…”