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

Abstract

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 μM). 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.