10.1021/jm048995+.s001 Venkat R. Macherla Venkat R. Macherla Scott S. Mitchell Scott S. Mitchell Rama Rao Manam Rama Rao Manam Katherine A. Reed Katherine A. Reed Ta-Hsiang Chao Ta-Hsiang Chao Benjamin Nicholson Benjamin Nicholson Gordafaried Deyanat-Yazdi Gordafaried Deyanat-Yazdi Bao Mai Bao Mai Paul R. Jensen Paul R. Jensen William F. Fenical William F. Fenical Saskia T. C. Neuteboom Saskia T. C. Neuteboom Kin S. Lam Kin S. Lam Michael A. Palladino Michael A. Palladino Barbara C. M. Potts Barbara C. M. Potts Structure−Activity Relationship Studies of Salinosporamide A (NPI-0052), a Novel Marine Derived Proteasome Inhibitor American Chemical Society 2005 Halogen exchange insight chloroethyl group stereochemical modifications analogue Relationship NF Marked reductions activation assay relationship replacement unhalogenated substituents finding cyclohexene ring epoxidation proteasome inhibition Novel Marine Derived Proteasome Inhibitor Salinosporamide cytotoxicity potency NPI attenuated activity proteasome inhibitor novel series 2005-06-02 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Structure_Activity_Relationship_Studies_of_Salinosporamide_A_NPI_0052_a_Novel_Marine_Derived_Proteasome_Inhibitor/3373810 Salinosporamide A (<b>1</b>, 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.