Structure−Activity Relationship Studies
of Salinosporamide A (NPI-0052), a Novel
Marine Derived Proteasome Inhibitor

Macherla, Venkat R.; Mitchell, Scott S.; Manam, Rama Rao; Reed, Katherine A.; Chao, Ta-Hsiang; Nicholson, Benjamin; Deyanat-Yazdi, Gordafaried; Mai, Bao; Jensen, Paul R.; Fenical, William F.; T. C. Neuteboom, Saskia; Lam, Kin S.; Palladino, Michael A.; C. M. Potts, Barbara

doi:10.1021/jm048995+.s001

jm048995+_si_001.pdf (130.06 kB)

Structure−Activity Relationship Studies of Salinosporamide A (NPI-0052), a Novel Marine Derived Proteasome Inhibitor

journal contribution

posted on 2005-06-02, 00:00 authored by 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 F. Fenical, Saskia T. C. Neuteboom, Kin S. Lam, Michael A. Palladino, Barbara C. M. Potts

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-κB 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.