Salinosporamide A (NPI-0052; 1) is a potent 20S proteasome inhibitor that is currently in clinical trials for the treatment of various cancers [1,2].  A unique structural feature of this marine-derived proteasome inhibitor compared to other beta-lactone-gamma-lactams is the chloroethyl substituent, which imparts enhanced potency against isolated proteasomes and increased cytotoxicity against tumor cell lines [1,3].  In 2006, the crystal structure of 1 in complex with the yeast 20S proteasome demonstrated that the chlorine of 1 acts as a leaving group within the proteasome active sites; we hypothesized that this renders the inhibitor irreversibly bound [4].  To substantiate our hypothesis, we designed and synthesized analogs bearing substituents representing a range of leaving group potentials and evaluated them for inhibition of isolated rabbit 20S proteasomes, as well as cytoxicity and proteasome inhibition in human RPMI-8226 multiple myeloma cells.  Duration of proteasome inhibition was evaluated under conditions of dialysis for the various proteasome-inhibitor complexes.  We further compared ³H-1 and its deschloro analog in terms of relative cell uptake and in vivo activity.  These studies highlight the contribution of the halogen leaving group of 1 to prolonged proteasome inhibition and potency. 
1.  Feling et al. Angew.Chem. Int. Ed. 2003, 42, 355-357.
2.  Chauhan et al. Cancer Cell 2005, 8, 407-419.
3.  Macherla et al. J. Med. Chem. 2005, 48, 3684-3687.
4.  Groll et al. J. Am. Chem. Soc. 2006, 128, 5136-5141.