Didehydro-Cortistatin A Inhibits HIV-1 by Specifically Binding to the Unstructured Basic Region of Tat.

The intrinsically disordered HIV-1 Tat protein binds the viral RNA transactivation response structure (TAR), which recruits transcriptional cofactors, amplifying viral mRNA expression. Limited Tat transactivation correlates with HIV-1 latency. Unfortunately, Tat inhibitors are not clinically available.

Specific and prolonged proteasome inhibition dictates apoptosis induction by marizomib and its analogs.

Marizomib (NPI-0052) is a naturally derived irreversible proteasome inhibitor that potently induces apoptosis via a caspase-8 and ROS-dependent mechanism in leukemia cells. We aim to understand the relationship between the irreversible inhibition of the proteasome and induction of cell death in leukemia cells by using analogs of marizomib that display reversible and irreversible properties. We highlight the importance of sustained inhibition of at least two proteasome activities as being key permissive events for the induction of the apoptotic process in leukemia cells.

Proteasome regulator marizomib (NPI-0052) exhibits prolonged inhibition, attenuated efflux, and greater cytotoxicity than its reversible analogs.

The present study was undertaken to compare the cellular transport characteristics of [(3)H]NPI-0052 (1R,4R,5S)-4-(2-chloroethyl)-1-((S)-((S)-cyclohex-2-enyl)(hydroxy)methyl)-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione (marizomib; salinosporamide A) and [(3)H]NPI-0047 (1R,4R, 5S)-1-((S)-((S)-cyclohex-2-enyl)(hydroxy)methyl)-4-ethyl-5-methyl-6-oxa-2-azabicyclo[3.

Concise formal synthesis of (-)-salinosporamide A (marizomib) using a regio- and stereoselective epoxidation and reductive oxirane ring-opening strategy.

Expedient access to a highly functionalized 2-pyrrolidinone (8), the gamma-lactam core of 20S proteasome inhibitor (-)-salinosporamide A (marizomib; NPI-0052; 1), using a regio- and stereoselective epoxide formation/reductive oxirane ring-opening strategy is presented. Notably, the sequential construction of the C-4, C-3, and C-2 stereocenters of 1 in a completely stereocontrolled fashion is a key feature of streamlining the synthesis of intermediate 12. A related strategy is also discussed.

Snapshots of the fluorosalinosporamide/20S complex offer mechanistic insights for fine tuning proteasome inhibition.

Many marketed drugs contain fluorine, reflecting its ability to modulate a variety of biological responses. The unique 20S proteasome inhibition profile of fluorosalinosporamide compared to chlorinated anticancer agent salinosporamide A (NPI-0052) is exemplary and relates to each halogen's leaving group potential. Crystal structures of fluoro-, hydroxy-, and bromosalinosporamide in complex with the yeast 20S proteasome core particle (CP) provide mechanistic insights into ligand binding and leaving group elimination and the ability to fine-tune the duration of proteasome inhibition.

Antiprotealide is a natural product.

Large-scale fermentation of the marine actinomycete Salinispora tropica for production of salinosporamide A (NPI-0052; 1) clinical trials materials provided crude extracts containing minor secondary metabolites, including salinosporamide B (2) and a new congener, 3. Spectroscopic characterization revealed that 3 is identical to antiprotealide, a molecular hybrid of 20S proteasome inhibitors 1 and omuralide (4) not previously described as a natural product. Analysis of crude extracts from shake flask cultures of three wild-type S.

Leaving groups prolong the duration of 20S proteasome inhibition and enhance the potency of salinosporamides.

Salinosporamide A ( 1 (NPI-0052)) is a potent, monochlorinated 20S proteasome inhibitor in clinical trials for the treatment of cancer. To elucidate the role of the chlorine leaving group (LG), we synthesized analogues with a range of LG potentials and determined their IC 50 values for inhibition of chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-like (C-L) activities of 20S proteasomes. Proteasome activity was also determined before and after attempted removal of the inhibitors by dialysis.

Seawater requirement for the production of lipoxazolidinones by marine actinomycete strain NPS8920.

A novel marine actinomycete strain NPS8920 produces a new class of 4-oxazolidinone antibiotics lipoxazolidinone A, B and C. Lipoxazolidinone A possesses good potency (1-2 microg/mL) against drug-resistant pathogens methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). Strain NPS8920 exhibits different morphologies in both agar and submerged cultures.

Lipoxazolidinones A, B, and C: antibacterial 4-oxazolidinones from a marine actinomycete isolated from a Guam marine sediment.

Marine actinomycete strain NPS008920, a member of the new genus Marinispora, was isolated from a sediment sample collected in Cocos Lagoon, Guam. In natural sea water containing media, the strain produced a series of novel 2-alkylidene-5-alkyl-4-oxazolidinones, lipoxazolidinone A (1), B (2), and C (3). Compounds 1- 3 showed broad spectrum antimicrobial activity similar to that of the commercial antibiotic linezolid (Zyvox), a 2-oxazolidinone.

Enantioselective total synthesis of (-)-Salinosporamide A (NPI-0052).

A novel enantioselective total synthesis of 20S proteasome inhibitor Salinosporamide A (NPI-0052; 1) is presented. Key features include intramolecular aldol cyclization of 6 to simultaneously generate the three chiral centers of advanced intermediate 5, cyclohexene ring addition using B-2-cyclohexen-1-yl-9-BBN, and inversion of the C-5 stereocenter by oxidation followed by enantioselective enzymatic reduction.

Glaciapyrroles A, B, and C, pyrrolosesquiterpenes from a Streptomyces sp. isolated from an Alaskan marine sediment.

A Streptomyces sp. (NPS008187) isolated from a marine sediment collected in Alaska was found to produce three new pyrrolosesquiterpenes, glyciapyrroles A (1), B (2), and C (3), along with the known diketopiperazines cyclo(leucyl-prolyl) (4), cyclo(isoleucyl-prolyl) (5), and cyclo(phenylalanyl-prolyl) (6). The structures of 1, 2, and 3 were established using spectroscopic methods.

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.