Our recent efforts to develop photoresponsive G4 ligands found that a highly rigid bispyridinium stiff-stilbene E-II (Figure ), was a very efficient G-quadruplex binder in the planar E-configuration even in physiologically-relevant conditions of high ionic strength and inactive in the bent Z-configuration. Ligand E-II was able to fuel the reversible unfolding of G4 DNA under Na + -rich conditions, thus enabling a way to control G4 topology on demand using light an external stimulus. A key drawback of the system, however, was that in aqueous conditions the oxidative fragmentation of the stiff-stilbene core rendered the phototriggered process irreversible, and thus repeated additions of the ligand were required in order to fuel multiple switching cycles of DNA topology. Subsequently, we found that dithienylethene derivatives o-/c-IV display excellent photochromic properties and switchable binding modes towards G4 DNA by toggling the ligand between the open and closed forms with photoirradiation, although the change in binding mode did deliver the significant change in binding affinity that is likely necessary to realise the majority of potential applications. In light of the results of the aforementioned studies, we reasoned that the fully reversible switching of G4 ligand binding in physiological conditions required a chemotype that combined the rigidity of the stiff-stilbene scaffold with the photostability of the azobenzene chromophore. Recently, cyclic bridged azobenzene derivatives have been investigated by Zeller, Herges, Temps and co-workers, and later by Trauner and colleagues. These derivatives display excellent photophysical properties and prove to be photoswitchable over many switching cycles without photofatigue. Unlike the most commonly employed photochromic azobenzenes, which are thermodynamically more stable in their elongated transform, cyclic azobenzene photoswitches feature the diazene motif constrained within an eightmembered ring, and are thermodynamically more stable in their "bent" cis form, where the ring adopts a relaxed confirmation, rather than the unusual sterically-demanding twisted conformation observed in the trans state. Depending on the substitution pattern and electronic nature of the substituents, the thermal back-isomerization from the trans to the cis can vary from nanoseconds to days under physiological conditions. These photoswitches have recently emerged as promising motifs to be incorporated into a range of photopharmaceuticals including into oligonucleotides for the photo-regulation of DNA hybridization. However, the use of the cyclic azobenzene fragment as the basis DNAtargeting small molecules has not yet been explored. In the context of our work, we were very curious to investigate the binding of trans and cis bridged azobenzene derivatives to DNA structures, particularly G4s, for several reasons. Firstly, the high photostability of the scaffold coupled with its increased rigidity (compared to its 'free' azobenzene analogue) appeared to combine the best features of the photoresponsive G4 ligands developed to date. Moreover, the very unusual, twisted, geometry of the trans form of the scaffold represents an exceptionally unique chemotype for DNA recognition: of the hundreds of G-quadruplex ligands reported to date, to the best of our knowledge there is no example of a G4 binding fragment that possesses this type of molecular geometry.