Synthesis and Structure-Activity Relationship of Marinostatin, An Ester-Linked Serine Protease Inhibitor

摘要

@@ Marinostatin (MST) isolated from a marine organism is a serine protease inhibitor having two ester linkages that are formed between the /?-hydroxyl and β-carboxyl groups, Thr3-Asp9 and Ser8-Asp11 MST strongly inhibits subtilisin at an enzyme-inhibitor ratio of 1:1, but not trypsin[1]. Its scissile peptide bond is located between Met4 and Arg5 and its inhibitory potential is greatly attributed to hydrogen bonding between the backbone NH proton of the P1' residue, Arg5, and the carbonyl oxygen of the ester linkage with Thr3-Asp9[2]. MST was synthesized by a regioselective esterification procedure employing two sets of orthogonally removable side-chain protecting groups for Asp and Ser/Thr (Figure 1).