Photocontrolled activation of doubly -nitrobenzyl-protected small molecule benzimidazoles leads to cancer cell death

Artificial biomimetic chloride anionophores have shown promising applications as anticancer scaffolds. Importantly, stimuli-responsive chloride transporters that can be selectively activated inside the cancer cells to avoid undesired toxicity to normal, healthy cells are very rare. Particularly, light-responsive systems promise better applicability for photodynamic therapy because of their spatiotemporal controllability, low toxicity, and high tunability. Here, in this work, we report o -nitrobenzyl-linked, benzimidazole-based singly and doubly protected photocaged protransporters 2a , 2b , 3a , and 3b , respectively, and benzimidazole-2-amine-based active transporters 1a-1d . Among the active compounds, trifluoromethyl -based anionophore 1a showed efficient ion transport activity (EC 50 = 1.2 ± 0.2 μM). Detailed mechanistic studies revealed Cl − /NO 3 − antiport as the main ion transport process. Interestingly, double protection with photocages was found to be necessary to achieve the complete "OFF-state" that could be activated by external light. The procarriers were eventually activated inside the MCF-7 cancer cells to induce phototoxic cell death. A double o -nitrobenzyl-linked benzimidazole-2-amine-based protransporter is reported for its photoactivation by 400 nm light leading to efficient OFF-to-ON anion antiport and efficient cancer cell death.