Chem. Pharm. Bull., 47(1),1-10, January 1999
Lactacystin (1) and the related b-lactone omuralide (2) are remarkably selective and potent irreversible inhibitors of the 20S proteasome, a large polymolecular protein machine which is responsible for the degradation of ubiquitin-labeled proteins. Because of this fact 1 and 2 have emerged as important tools in biochemistry and cell biology. The challenge of synthesis has been accepted by several research groups with the result that 1 and 2 and their analogs can now be synthesized by a variety of synthetic approaches. This review summarizes the synthetic processes which have been developed to date for the production of such compounds. The study of biological activity of analogs of 1 and 2 has clearly defined the structural features which are responsible for the potency of 1 and 2, as described in the closing section of this account. It is concluded that 1 and 2 are nearly optimal for the irreversible inactivation of the 20S proteasome.
Key words lactacystin; omuralide; synthesis; bioactivity; proteasome; inhibition