A Short and Efficient Synthesis of (-)-7-Methylomuralide, a Potent Proteasome Inhibitor

摘要

Lactacystin (1) was discovered by Omura et al. using an in vitro screen for secondary metabolites that exhibit nerve growth factor-like activity against a murine neuronal cell line. Subsequently, it was determined that the observed stimulation of neurite outgrowth shown by 1 stemmed from its inhibition of the 20S proteasome by acylation mainly at the N-terminal threonine of the β5 (chymotryptic) subunit. The active small molecule in this process is the β-lactone omuralide (clasto-lactacystin, 2), of which 1 is actually a precursor.