Spiro beta-lactone-based proteasome inhibitors were discovered in the context of
an asymmetric catalytic total synthesis of the natural product (+)-lactacystin
(1). Lactone 4 was found to be a potent inhibitor of the 26S proteasome, while
its C-6 epimer (5) displayed weak activity. Crystallographic studies of the two
analogues covalently bound to the 20S proteasome permitted characterization of
the important stabilizing interactions between each inhibitor and the
proteasome's key catalytic N-terminal threonine residue. This structural data
support the hypothesis that the discrepancy in potency between 4 and 5 may be
due to differences in the hydrolytic stabilities of the resulting acyl enzyme
complexes.
