G-quadruplex (G4) DNA structures are linked to key biological processes and human diseases. Small molecules that target specific G4 DNA structures and signal their presence would therefore be of great value as chemical research tools with potential to further advance towards diagnostic and therapeutic developments. However, the development of these types of specific compounds remain as a great challenge. In here, we have developed a compound with ability to specifically signal a certain c-MYC G4 DNA structure through a fluorescence light-up mechanism. Despite the compound's two binding sites on the G4 DNA structure, only one of them result in the fluorescence light-up effect. This G-tetrad selectivity proved to originate from a difference in flexibility that affected the binding affinity and tilt the compound out of the planar conformation required for the fluorescence light-up mechanism. The intertwined relation between the presented factors is likely the reason for the lack of examples using rational design to develop compounds with turn-on emission that specifically target certain G4 DNA structures. However, this study shows that it is indeed possible to develop such compounds and present insights into the molecular details of specific G4 DNA recognition and signaling to advance future studies of G4 biology.

The plant flavonoid quercetin (Que) binds more efficiently to VEGF G-quadruplex DNA (G4–DNA) compared to double stranded DNA as well as other G4–DNAs.

We have designed and synthesized a novel fluorescent molecular probe using the Cu(I)-catalyzed Huisgen cycloaddition of 1,3-diethynyl-6-fluoroisoquinoline with 1-(2-azidoethyl)pyrrolidine. This water soluble “click” fluorescent chemosensor displays good sensitivity towards heavy and transition metal ions. It shows pronounced fluorescence enhancement and high selectivity for Zn²⁺ over other biologically relevant metal ions in water at pH 7.0. The fluorescence response of the bis-triazole derivative in the presence of Zn²⁺ is switchable and reversible as a function of pH. The chemosensor also exhibits fluorescence quenching with Fe²⁺ and Cu²⁺ in water at pH 7.0. A modified YES logic gate property has been proposed using the “turn-on” and “turn-off” behavior of the bis-triazole with Zn²⁺ and Fe²⁺. The sensor is cell membrane permeable and applicable for intracellular Zn²⁺ imaging.