Investigation into the P sub(3) Binding Domain of m-Calpain Using Photoswitchable Diazo- and Triazene-dipeptide Aldehydes: New Anticataract Agents

The photoswitchable N-terminal diazo and triazene-dipeptide aldehydes 8a-d, 10a,b, and 17a,b present predominantly as the (E)-isomer, which purportedly binds deep in the S sub(3) pocket of calpain. All compounds are potent inhibitors of m-calpain, with 8b being the most active (IC sub(50) of 35 nM). The diazocontaining inhibitors 8a, 8c, and 10a were irradiated at 340 nm to give a photostationary state enriched in the (Z)-isomer, and in all cases, these were less active. The most water soluble triazene 17a (IC sub(50) of 90 nM) retards calpain-induced cataract formation in lens culture.