Function-oriented biosynthesis of beta-lactone proteasome inhibitors in Salinispora tropica

  • J Med Chem. 2009 Oct 8;52(19):6163-7. doi: 10.1021/jm901098m.
Markus Nett  1 ,  Tobias A M Gulder ,  Andrew J Kale ,  Chambers C Hughes ,  Bradley S Moore
Affiliations
  • 1. Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California 92093, USA.
PMID: 19746976 DOI: 10.1021/jm901098m
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.