Cyanobacterial peptides as a prototype for the design of cathepsin D inhibitors

Cathepsin D (Cath D) is overexpressed and secreted in a number of solid tumors and involved in the progress of tumor invasion, proliferation, metastasis, and apoptosis. Inhibition of Cath D is regarded as an attractive pathway for the development of novel anticancer drugs. Our previous studies revealed that tasiamide B, a cyanobacterial peptide that contained a statine‐like unit, exhibited good inhibition against Cath D and other aspartic proteases. Using this natural product as prototype, we designed and synthesized three new analogs, which bear isophthalic acid fragment at the N‐terminus and isobutyl amine ( 1 ), cyclopropyl amine ( 2 ), or 3‐methoxybenzyl amine ( 3 ) moiety at the C‐terminus. Enzymatic assays revealed that all these three compounds showed moderate‐to‐good inhibition against Cath D, with IC₅₀s of 15, 884, and 353 nM, respectively. Notably, compound 1 showed extreme selectivity for Cath D with 576‐fold over Cath E and 554‐fold over BACE1, which could be a valuable template for the design of highly potent and selective Cath D inhibitors. Additionally, compound 1 showed moderated activity against HeLa cell lines with IC₅₀ of 41.8 μM. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.