salinosporamide-b and marizomib

Actinomycetes produce structurally unique secondary metabolites with pharmaceutically essential bioactivities. Salinispora, an obligate marine actinomycete, produces structurally varied and unique secondary metabolites. There is plenty of scope for development of drugs from the novel compounds isolated from Salinispora. Anticancer, antibacterial and anti-protozoa activities have been shown for Salinosporamides A, B and C, the secondary metabolites identified from Salinispora, which make them interesting subjects for further extended biological activity prediction.. An in silico ligand based-pharmacophore approach was used for the prediction of extended biological targets for salinosporamide A, B and C. Pharmacophore models of salinosporamide A, B and C were generated individually and screened against known drug databases. The drugs with best fitness score were shortlisted, and their respective targets pertaining to their bioactivity were retrieved. The predicted biological drug targets were docked with salinosporamide A, B and C for validation.. The glucocorticoid receptor and methionine aminopeptidase 2 showed good docking score and binding energy with salinosporamide A, B and C. Molecular dynamics studies of the protein-ligand complexes showed stable interactions suggesting that the predicted new targets for salinosporamides might be promising.. The glucocorticoid receptor and methionine aminopeptidase 2 could be possible new drug targets of bioactivity of salinosporamides. These proteins could be the druggable targets for antiinflammatory and anticancer activity of salinosporamides.

Topics: Actinobacteria; Aminopeptidases; Drug Discovery; Humans; Lactams; Lactones; Ligands; Metalloendopeptidases; Molecular Docking Simulation; Protein Binding; Pyrroles; Receptors, Glucocorticoid

Topics: Actinomycetales; Chromatography, High Pressure Liquid; Cobalt; Culture Media; Fermentation; Lactams; Lactones; Molecular Conformation; Pyrroles; Vitamin B 12

Topics: Binding Sites; Biological Factors; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Genetic Engineering; Humans; Hydrocarbons, Fluorinated; Lactams; Lactones; Proteasome Inhibitors; Pyrroles; Saccharomyces cerevisiae; Structure-Activity Relationship

In this paper, we described the development of a potassium-chloride-based-salt formulation containing low sodium concentrations (5.0 to 11 mM) to support the growth of Salinispora tropica strain NPS21184 and its production of salinosporamide A (NPI-0052). The sodium present in the media was essentially derived from the complex nitrogen sources Hy Soy, yeast extract, and peptone used in the media. We demonstrated that good growth rate and yield of S. tropica strain NPS21184 were detected in both agar and liquid media containing the potassium-chloride-based-salt formulation with sodium concentration as low as 5.0 mM, significantly less than the critical seawater-growth requirement concentration of 50 mM sodium for a marine microorganism. We also observed good production of NPI-0052 (176 to 243 mg/l) by S. tropica strain NPS21184 grown in production media containing the potassium chloride-based-salt formulation. The production of deschloro analog, salinosporamide B (NPI-0047), was significantly lower in the low-sodium-salt-formulation medium than in the high-sodium-salt-formulation media. We demonstrated that while S. tropica strain NPS21184 is a novel marine actinomycete that requires high salt content for growth, it does not require sodium-chloride-based seawater-type media for growth and production of NPI-0052.

Topics: Culture Media; Fermentation; Industrial Microbiology; Lactams; Lactones; Micromonosporaceae; Pyrroles; Seawater; Sodium Compounds

[structure: see text] Feeding experiments with stable isotopes established that the potent 20S-proteasome inhibitors salinosporamide A and B are biosynthesized in the marine bacterium Salinispora tropica from three biosynthetic building blocks, namely, acetate, beta-hydroxy-2'-cyclohexenylalanine, and either butyrate or a tetrose-derived chlorinated molecule. The unexpected observation that the chlorinated four-carbon residue in salinosporamide A is derived from a different metabolic origin than the non-chlorinated four-carbon unit in salinosporamide B is suggestive of a convergent biosynthesis to these two anticancer natural products.

Topics: Amino Acids; Lactams; Lactones; Magnetic Resonance Spectroscopy; Micromonosporaceae; Molecular Structure; Oceans and Seas; Peptides; Pyrroles

Feeding sodium butyrate (0.25-1 mg/ml) to cultures of Salinispora tropica NPS21184 enhanced the production of salinosporamide B (NPI-0047) by 319% while inhibiting the production of salinosporamide A (NPI-0052) by 26%. Liquid chromatography mass spectrometry analysis of the crude extract from the strain NPS21184 fed with 0.5 mg/ml sodium [U-(13)C(4)]butyrate indicated that butyrate was incorporated as a contiguous four-carbon unit into NPI-0047 but not into NPI-0052. Nuclear magnetic resonance analysis of NPI-0047 and NPI-0052 purified from the sodium [U-(13)C(4)]butyrate-supplemented culture extract confirmed this incorporation pattern. The above finding is the first direct evidence to demonstrate that the biosynthesis of NPI-0047 is different from NPI-0052, and NPI-0047 is not a precursor of NPI-0052.

Topics: Butyric Acid; Lactams; Lactones; Magnetic Resonance Spectroscopy; Micromonosporaceae; Pyrroles

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.

Topics: Actinobacteria; Animals; Antineoplastic Agents; Cell Line; Cell Line, Tumor; Humans; Lactones; Marine Biology; NF-kappa B; Proteasome Inhibitors; Pyrroles; Rabbits; Stereoisomerism; Structure-Activity Relationship