Structure-activity relationship studies of salinosporamide A (NPI-0052), a novel marine derived proteasome inhibitor

  • J Med Chem. 2005 Jun 2;48(11):3684-7. doi: 10.1021/jm048995+.
Venkat R Macherla  1 ,  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
Affiliations
  • 1. Nereus Pharmaceuticals, Inc., 10480 Wateridge Circle, San Diego, California 92121, USA.
PMID: 15916417 DOI: 10.1021/jm048995+
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.