title: Structure-activity relationship studies of salinosporamide A (NPI-0052), a novel marine derived proteasome inhibitor.
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.
authors.affiliation: Nereus Pharmaceuticals, Inc., 10480 Wateridge Circle, San Diego, California 92121, USA.
authors.forename: Venkat R
authors.initials: VR
authors.lastname: Macherla
authors.forename: Scott S
authors.initials: SS
authors.lastname: Mitchell
authors.forename: Rama Rao
authors.initials: RR
authors.lastname: Manam
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Reed
authors.forename: Ta-Hsiang
authors.initials: TH
authors.lastname: Chao
authors.forename: Benjamin
authors.initials: B
authors.lastname: Nicholson
authors.forename: Gordafaried
authors.initials: G
authors.lastname: Deyanat-Yazdi
authors.forename: Bao
authors.initials: B
authors.lastname: Mai
authors.forename: Paul R
authors.initials: PR
authors.lastname: Jensen
authors.forename: William F
authors.initials: WF
authors.lastname: Fenical
authors.forename: Saskia T C
authors.initials: ST
authors.lastname: Neuteboom
authors.forename: Kin S
authors.initials: KS
authors.lastname: Lam
authors.forename: Michael A
authors.initials: MA
authors.lastname: Palladino
authors.forename: Barbara C M
authors.initials: BC
authors.lastname: Potts
mesh_terms: D039903:Actinobacteria; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008386:Marine Biology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D061988:Proteasome Inhibitors; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011758:Pyrroles; C475865:marizomib