Total synthesis and biological activity of lactacystin, omuralide and analogs.
Lactacystin (1) and the related beta-lactone omuralide (2) are remarkably selective 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 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 20 S proteasome.
Corey
E J
EJ
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Li
W D
WD
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002417:Cattle; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007769:Lactams; D007783:Lactones / Q000138:chemical synthesis*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship