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Structural analysis of spiro beta-lactone proteasome inhibitors.

ABSTRACT: 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.

SUBMITTER: Groll M

PROVIDER: S-EPMC2587002 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Structural analysis of spiro beta-lactone proteasome inhibitors.

Groll Michael M Balskus Emily P EP Jacobsen Eric N EN

Journal of the American Chemical Society 20081017 45

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-ter ...[more]

PMID: 18928262

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