Diamide Strapped Calixpyrroles. Synthetic Ion Pair Transporters That Induce Apoptosis

The synthesis, ion recognition function, and apoptosis-inducing activity of two pyridine diamide strapped calix[4]pyrroles is described. These systems act as sodium chloride transporters in liposomal models and in cancer cells. They induce cancer cell death by increasing intracellular chloride and sodium ion concentrations. This response can be abrogated when either ion is removed from the extracellular media. However, control systems, lacking the diamide functionality and having poor ion transport activities, have very low cytotoxicity. Results obtained from cell experiments show that ion pair transporters induce caspase activation via sodium chloride influx but do not activate AIF-associated caspase-independent apoptotic pathways. These compounds also lead to an increased level of reactive oxygen species production in cancer cells. They thus represent an attractive new approach to regulating biological processes by modulating ion concentrations that are normally controlled tightly via homeostasis of cells.