Function-oriented Biosynthesis of Beta-lactone Proteasome Inhibitors in Salinispora Tropica

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2009 Sep 15

PMID 19746976

Citations 30

Authors

Markus Nett

Tobias A M Gulder

Andrew J Kale

Chambers C Hughes

Bradley S Moore

Affiliations

Soon will be listed here.

Abstract

The natural proteasome inhibitor salinosporamide A from the marine bacterium Salinispora tropica is a promising drug candidate for the treatment of multiple myeloma and mantle cell lymphoma. Using a comprehensive approach that combined chemical synthesis with metabolic engineering, we generated a series of salinosporamide analogues with altered proteasome binding affinity. One of the engineered compounds is equipotent to salinosporamide A in inhibition of the chymotrypsin-like activity of the proteasome yet exhibits superior activity in the cell-based HCT-116 assay.

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