Fast photo-deactivation of chloride transport and cytotoxicity mediated by squaramides

The ability to control anion transporters with precision is crucial to maximise their therapeutic potential while mitigating collateral damage to healthy cells. Consequently, there is a growing interest in light-regulated anion transporters, which offer the advantage of spatio-temporal control over their activity. We have previously reported that the chloride transport activity of an electron-poor squaramide can be inhibited by UV irradiation (365 nm), probably due to the photo-transformation of the transporter. Herein we present a series of diaryl squaramides containing different electron-withdrawing substituents. Using liposome-based assays, all compounds, with similar chloride affinities, have shown to be active chloride transporters at a relatively low concentration (1:10k transporter-lipid ratio). We have studied the efficiency of the light-induced deactivation process, observing how the nature of the electron-withdrawing groups on the aryl rings has a strong effect on the time of irradiation required to completely inhibit the transport activity of the compounds. Remarkably, efficient deactivations have been observed with cyano-substituted squaramides, which have showed complete loss of activity after only 1-2 s of irradiation. Finally, we have performed cell viability studies that show how the cytotoxicity of squaramides can be reduced by irradiation, which can be attributed to the deactivation of an anion transport process in the cell membrane.