Structural Congeners of Izenamides Responsible for Cathepsin D Inhibition: Insights from Synthesis-Derived Elucidation

This study aimed to elucidate the structural congeners of natural izenamides A, B, and C (1-3) responsible for cathepsin D (CTSD) inhibition. Structurally modified izenamides were synthesized and biologically evaluated, and their biologically important core structures were identified. We confirmed that the natural statine (Sta) unit (3S,4S)-gamma-amino-beta-hydroxy acid is a requisite core structure of izenamides for inhibition of CTSD, which is closely related to the pathophysiological roles in numerous human diseases. Interestingly, the statine-incorporated izenamide C variant (7) and 18-epi-izenamide B variant (8) exhibited more potent CTSD-inhibitory activities than natural izenamides.

Automated summary

This study aimed to elucidate the structural congeners of natural izenamides A, B, and C (1-3) responsible for cathepsin D (CTSD) inhibition. The biologically important core structures of the synthesized izenamide variants were identified. It was confirmed that the natural statine (Sta) unit is a requisite core structure for CTSD inhibition, and statine-incorporated izenamide C variant and 18-epi-izenamide B variant showed more potent CTSD-inhibitory activities than natural izenamides.