Journal of medicinal and pharmaceutical chemistry 2009-10-08

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

Markus Nett, Tobias A M Gulder, Andrew J Kale, Chambers C Hughes, Bradley S Moore

Index: J. Med. Chem. 52(19) , 6163-7, (2009)

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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.