Prevention of Mitochondrial Membrane Permeabilization and Pancreatic β‐Cell Death by an Enantioenriched, Macrocyclic Small Molecule

Abstract

Abstract Mitochondria produce the majority of cellular energy through the process of oxidative phosphorylation and play a central role in regulating the functionality and survival of eukaryotic cells. Under physiological stress, mitochondrial membrane permeabilization results in the release of apoptogenic material such as cytochrome c in the cytoplasm, which thereby initiates caspase activation and the consequent cell death. In our present study, we screened a series of compounds for their ability to inhibit mitochondrial membrane permeabilization and to prevent cytochrome c release during the endoplasmic reticulum stress in cultured pancreatic β‐cells. Three benzofuran‐based macrocyclic small molecules, that is, 2.4c , c104 , and c108 , were found to restore the depolarization of mitochondrial membrane potential and to prevent the release of cytochrome c from mitochondria. Interestingly, the acyclic precursor of 2.4c (i.e., 2.3c ) did not show any effect, whereas the macrocyclic derivative obtained by utilizing ring‐closing metathesis as the “stitching technology” led to this function. The macrocyclic architecture seems to play a crucial role in presenting various functional moieties in the right orientation to observe this effect.