Pyrrole-Linked Benzimidazolyl Hydrazone Self-Assembly Forms HCl Channels and Induces Apoptosis in Cancer Cells

Abstract

Modulation of intracellular chloride ion concentration by artificially developed ion transporters has been known to induce apoptosis in cancer cells. However, most of these transporters cause harm to healthy cells as well, limiting their applicability in real biological systems. Here, we report a pyrrole-linked benzimidazolyl-hydrazone that self-assembles to form a nanochannel assembly across the lipid bilayer, enabling the selective translocation of HCl, a system rarely reported in the literature. The channel shows an extraordinarily high HCl transport activity with an EC50 value as low as 0.016 mol%, relative to lipid. We demonstrate solid-state evidence that compound 1 self-assembles in the presence of HCl to produce organized arrays that include chloride-filled and water-filled channels. The formation of a stable HCl channel across the lipid bilayer membrane was verified through electrophysiological experiments, detailed molecular dynamics (MD) simulations, and quantum mechanical calculations. When tested in cellular systems, the compound showed pronounced toxicity toward cancerous cell lines while remaining relatively nontoxic to cell lines of non-cancerous origin. Interestingly, compound 1 was also found to inhibit the growth and proliferation of MCF-7-derived 3D spheroids with higher efficiency when compared to the commercially available anticancer drug─doxorubicin (DOX).