Structure-activity relationship studies of salinosporamide A (NPI-0052), a novel marine derived proteasome inhibitor.
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.
Macherla
Venkat R
VR
Nereus Pharmaceuticals, Inc., 10480 Wateridge Circle, San Diego, California 92121, USA.
Mitchell
Scott S
SS
Manam
Rama Rao
RR
Reed
Katherine A
KA
Chao
Ta-Hsiang
TH
Nicholson
Benjamin
B
Deyanat-Yazdi
Gordafaried
G
Mai
Bao
B
Jensen
Paul R
PR
Fenical
William F
WF
Neuteboom
Saskia T C
ST
Lam
Kin S
KS
Palladino
Michael A
MA
Potts
Barbara C M
BC
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
D000970:Antineoplastic Agents; D007783:Lactones; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011758:Pyrroles; C475865:marizomib