Total synthesis of marinostatin, a serine protease inhibitor isolated from the marine bacterium Pseudoallteromonas sagamiensis

Marinostatin (MST) (1) isolated from a marine organism is a serine protease inhibitor consisting of 12 amino acids with two internal ester linkages that are formed between the β-hydroxyl and β-carboxyl groups, Thr3-Asp9 and Ser8-Asp11. We synthesized MST by a regioselective esterification procedure employing two sets of orthogonally removable protecting groups at the side-chains of Asp and Ser/Thr. We optimized the esterification conditions to preferentially form the intramolecular ester linkages without any significant aspartimide (Asi) formation at Asp9 and Asp11. The inhibitory potency of the synthetic MST against subtilisin (Ki, 0.6 nM) was comparable with a reported value for native MST (1.5 nM).

Graphical abstractA total synthesis of marinostatin having two internal ester linkages was first achieved by a regioselective esterification employing two sets of orthogonally removable side-chain protecting groups for Asp and Ser/Thr.Download full-size image