| Summary: | This study aimed to elucidate the structural congeners of natural izenamides A, B, and C (<b>1</b>–<b>3</b>) 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 (3<i>S</i>,4<i>S</i>)-γ-amino-β-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 (<b>7</b>) and 18-<i>epi</i>-izenamide B variant (<b>8</b>) exhibited more potent CTSD-inhibitory activities than natural izenamides.
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