Abastatins A-C: Cathepsin D-Inhibitory Depsipeptides From a Marine Okeania sp. Cyanobacterium

Statine [(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (Sta)] is a γ-amino acid produced by several microorganisms, including actinomycetes and cyanobacteria. Sta-containing natural products are known to inhibit cathepsin D, a promising therapeutic target for cancer and neurodegenerative diseases. In this study, three new Sta-containing natural products, abastatins A-C, were isolated from a marine Okeania sp. cyanobacterium collected in Japan. Their structures were unambiguously elucidated by spectroscopic analyses combined with derivatization and degradation reactions. To date, Sta-containing natural products have been discovered mainly from marine cyanobacteria; among them, abastatins A-C exhibit the most potent cathepsin D inhibitory activities reported thus far with IC₅₀ values in the picomolar range. In addition, we propose plausible docking poses for abastatins A-C bound to cathepsin D and describe a new structure-activity relationship that can enhance inhibitory potency against this enzyme.