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Syntheses and Biological Evaluation of (+)‐Lactacystin and Analogs
Author(s) -
Masse Craig E.,
Morgan Adam J.,
Adams Julian,
Panek James S.
Publication year - 2000
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/1099-0690(200007)2000:14<2513::aid-ejoc2513>3.0.co;2-d
Subject(s) - lactacystin , chemistry , proteasome , stereochemistry , combinatorial chemistry , proteasome inhibitor , biochemistry
Since its isolation in 1991, (+)‐lactacystin ( 1 ) has attracted considerable attention among leading synthesis laboratories due to its highly selective and potent inhibition of the 20 S proteasome. The syntheses of this molecule described herein demonstrate several important strategies in the area of acyclic stereocontrol including the use of chiral metal enolate and chiral allylmetal‐based bond construction methods. Several analogs of 1 and of the related β‐lactone 2 are also presented, which provide insight into the structure activity relationship relative to the molecule’s inhibition of the 20 S proteasome. Additionally, an analog of 2 is discussed regarding its clinical evaluation for the treatment of cerebral ischemia and stroke.