Structure−Activity Relationship Studies of Salinosporamide A (NPI-0052), a Novel Marine Derived Proteasome Inhibitor
Journal of Medicinal Chemistry2005Vol. 48(11), pp. 3684–3687
Citations Over TimeTop 10% of 2005 papers
Venkat R. Macherla, Scott S. Mitchell, Rama Rao Manam, Katherine A. Reed, Ta‐Hsiang Chao, Benjamin Nicholson, Gordafaried Deyanat‐Yazdi, Bao Mai, Paul R. Jensen, William Fenical, Saskia Neuteboom, Kin S. Lam, Michael A. Palladino, Barbara C. M. Potts
Abstract
Salinosporamide A (1, NPI-0052) is a potent proteasome inhibitor in development for treating cancer. In this study, a series of analogues was assayed for cytotoxicity, proteasome inhibition, and inhibition of NF-kappaB activation. Marked reductions in potency in cell-based assays accompanied replacement of the chloroethyl group with unhalogenated substituents. Halogen exchange and cyclohexene ring epoxidation were well tolerated, while some stereochemical modifications significantly attenuated activity. These findings provide insights into structure-activity relationships within this novel series.
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