Total synthesis and biological activity of lactacystin, omuralide and analogs

Lactacystin (1) and the related beta-lactone omuralide (2) are remarkably s elective and potent irreversible inhibitors of the 20 S 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 im portant tools in biochemistry and cell biology, The challenge of synthesis has been accepted by several research groups with the result that 1 and 2 a nd their analogs can now be synthesized by a variety of synthetic approache s. This review summarizes the synthetic processes which have been developed to date for the production of such compounds, The study of biological acti vity of analogs of 1 and 2 has clearly defined the structural features whic h are responsible for the potency of 1 and 2, as described in the closing s ection of this account, It is concluded that 1 and 2 are nearly optimal for the irreversible inactivation of the 20S proteasome.