G-quadruplex (G4) DNA structures are implicated in central biological processes and are considered promising therapeutic targets because of their links to human diseases such as cancer. However, functional details of...
G-quadruplex (G4)
DNA structures are widespread in the human genome
and are implicated in biologically important processes such as telomere
maintenance, gene regulation, and DNA replication. Guanine-rich sequences
with potential to form G4 structures are prevalent in the promoter
regions of oncogenes, and G4 sites are now considered as attractive
targets for anticancer therapies. However, there are very few reports
of small “druglike” optical G4 reporters that are easily
accessible through one-step synthesis and that are capable of discriminating
between different G4 topologies. Here, we present a small water-soluble
light-up fluorescent probe that features a minimalistic amidinocoumarin-based
molecular scaffold that selectively targets parallel G4 structures
over antiparallel and non-G4 structures. We showed that this biocompatible
ligand is able to selectively stabilize the G4 template resulting
in slower DNA synthesis. By tracking individual DNA molecules, we
demonstrated that the G4-stabilizing ligand perturbs DNA replication
in cancer cells, resulting in decreased cell viability. Moreover,
the fast-cellular entry of the probe enabled detection of nucleolar
G4 structures in living cells. Finally, insights gained from the structure–activity
relationships of the probe suggest the basis for the recognition of
parallel G4s, opening up new avenues for the design of new biocompatible
G4-specific small molecules for G4-driven theranostic applications.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.