Salinosporamides D-J from the marine actinomycete Salinispora tropica, bromosalinosporamide, and thioester derivatives are potent inhibitors of the 20S proteasome.
Salinosporamide A (NPI-0052; 3), a highly potent inhibitor of the 20S proteasome, is currently in phase I clinical trials for the treatment of cancer. During the course of purifying multigram quantities of 3 from Salinispora tropica fermentation extracts, several new salinosporamides were isolated and characterized, most of which represent modifications to the chloroethyl substituent at C-2. Specifically, 3 was isolated along with the known compound salinosporamide B (4), the previously undescribed methyl congener salinosporamide D (7), and C-2 epimers of 3 and 7 (salinosporamides F (9) and G (10), respectively). Salinosporamide I (13), in which the methyl group at the ring junction is replaced with an ethyl group, and the C-5 deshydroxyl analogue salinosporamide J (14), were also identified. Replacement of synthetic sea salt with sodium bromide in the fermentation media produced bromosalinosporamide (12), 4, and its C-2 epimer (11, salinosporamide H). In addition to these eight new salinosporamides, several thioester derivatives were generated semisynthetically. IC50 values for cytotoxicity against human multiple myeloma cell line RPMI 8226 and inhibition of the chymotrypsin-like (CT-L) activity of purified rabbit 20S proteasomes were determined for all compounds. The results indicate that thioesters may directly inhibit the proteasome, albeit with reduced potency compared to their beta-lactone counterparts.
Reed
Katherine A
KA
Nereus Pharmaceuticals, Inc., 10480 Wateridge Circle, San Diego, California 92121, USA.
Manam
Rama Rao
RR
Mitchell
Scott S
SS
Xu
Jianlin
J
Teisan
Sy
S
Chao
Ta-Hsiang
TH
Deyanat-Yazdi
Gordafaried
G
Neuteboom
Saskia T C
ST
Lam
Kin S
KS
Potts
Barbara C M
BC
D039903:Actinobacteria / Q000737:chemistry* / Q000254:growth & development; D001444:Bahamas; D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D008386:Marine Biology; D008968:Molecular Conformation; D015394:Molecular Structure; D061988:Proteasome Inhibitors; D011758:Pyrroles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; C475865:marizomib