Novel dual inhibitors of calpain and lipid peroxidation with enhanced cellular activity

A series of dipeptides with dual inhibitory activities on calpain and lipid peroxidation were prepared to target the intracellular calpain. This optimization program focused on the variations of the linker and the N-terminal amino acid of the peptidic core. Two compounds 6d-05 and 6d-08 exhibited potent intracellular calpain inhibition. The polar surface area and the number of rotors appeared to be critical descriptors to account for the behavior of these hybrid molecules in the cellular calpain assay.

The synthesis of hybrid molecules possessing calpain inhibitory and antioxidant properties is reported. Two of them, 6d-05 and 6d-08, exhibit potent intracellular calpain inhibition (IC50 = 0.6 μM). According to a theoretical calculation approach, the polar surface area and the number of rotors of the molecules adequately describe their cellular behavior.Figure optionsDownload as PowerPoint slide