Photocontrolled activation of doubly o-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 (EC50 = 1.2 +/- 0.2 mu M). Detailed mechanistic studies revealed Cl-/NO3- 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.

Automated summary

Artificial biomimetic chloride anionophores have potential applications in anticancer scaffolds. Stimuli-responsive chloride transporters that can be selectively activated inside cancer cells are rare. Light-responsive systems, with their spatiotemporal controllability, low toxicity, and high tunability, show promise for photodynamic therapy. In this work, o-nitrobenzyl-linked, benzimidazole-based protransporters and active transporters were studied, and one compound showed efficient ion transport activity. Detailed mechanistic studies revealed the main ion transport process and the necessity of double protection with photocages for complete activation by external light. The activated procarriers induced phototoxic cell death in MCF-7 cancer cells.