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| Names | |
|---|---|
| Preferred IUPAC name (1R,4R,5S)-4-(2-Chloroethyl)-1-{(S)-[(1S)-cyclohex-2-en-1-yl](hydroxy)methyl}-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione | |
| Other names Marizomib; NPI-0052 | |
| Identifiers | |
3D model (JSmol) | |
| ChEBI | |
| ChEMBL | |
| ChemSpider |
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| KEGG | |
| UNII | |
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| Properties | |
| C15H20ClNO4 | |
| Molar mass | 313.781 g/mol |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Salinosporamide A (Marizomib) is a potentproteasome inhibitor being studied as a potentialanticancer agent. It entered phase I humanclinical trials for the treatment ofmultiple myeloma, only three years after its discovery in 2003.[1][2] This marine natural product is produced by the obligatemarine bacteriaSalinispora tropica andSalinispora arenicola, which are found inocean sediment. Salinosporamide A belongs to a family of compounds, known collectively assalinosporamides, which possess a densely functionalized γ-lactam-β-lactonebicyclic core.
Salinosporamide A was discovered by William Fenical and Paul Jensen from Scripps Institution of Oceanography in La Jolla, CA. In preliminary screening, a high percentage of the organic extracts of culturedSalinispora strains possessed antibiotic and anticancer activities, which suggests that these bacteria are an excellent resource for drug discovery.Salinispora strain CNB-392 was isolated from a heat-treated marine sediment sample and cytotoxicity-guided fractionation of the crude extract led to the isolation of salinosporamide A. Although salinosporamide A shares an identical bicyclic ring structure withomuralide, it is uniquely functionalized. Salinosporamide A displayed potent in vitro cytotoxicity againstHCT-116 human colon carcinoma with an IC50 value of 11 ng mL-1. This compound also displayed potent and highly selective activity in the NCI's60-cell-line panel with a mean GI50 value (the concentration required to achieve 50% growth inhibition) of less than 10 nM and a greater than 4 log LC50 differential between resistant and susceptible cell lines. The greatest potency was observed againstNCI-H226 non-small cell lung cancer,SF-539 brain tumor,SK-MEL-28 melanoma, andMDA-MB-435 melanoma (formerly misclassified as breast cancer[3]), all with LC50 values less than 10 nM. Salinosporamide A was tested for its effects on proteasome function because of its structural relationship to omuralide. When tested against purified 20S proteasome, salinosporamide A inhibited proteasomal chymotrypsin-like proteolytic activity with an IC50 value of 1.3 nM.[4] This compound is approximately 35 times more potent than omuralide which was tested as a positive control in the same assay. Thus, the unique functionalization of the core bicyclic ring structure of salinosporamide A appears to have resulted in a molecule that is a significantly more potent proteasome inhibitor than omuralide.[1]
Salinosporamide A inhibits proteasome activity by covalently modifying the active site threonine residues of the 20S proteasome.[citation needed]
It was originally hypothesized that salinosporamide B was a biosynthetic precursor to salinosporamide A due to their structural similarities.[citation needed]
It was thought that the halogenation of the unactivated methyl group was catalyzed by a non-heme iron halogenase.[5][6] Recent work using13C-labeled feeding experiments reveal distinct biosynthetic origins of salinosporamide A and B.[5][7]
While they share the biosynthetic precursorsacetate and presumed β-hydroxycyclohex-2'-enylalanine (3), they differ in the origin of the four-carbon building block that gives rise to their structural differences involving thehalogen atom. A hybridpolyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) pathway is most likely the biosynthetic mechanism in whichacetyl-CoA and butyrate-derived ethylmalonyl-CoA condense to yield the β-ketothioester (4), which then reacts with (3) to generate the linear precursor (5).
The first stereoselective synthesis was reported by Rajender Reddy Leleti and E. J.Corey.[8] Later several routes to the total synthesis of salinosporamide A have been reported.[8][9][10][11]
In vitro studies using purified 20S proteasomes showed that salinosporamide A has lowerEC50 for trypsin-like (T-L) activity than doesbortezomib.In vivo animal model studies show marked inhibition of T-L activity in response to salinosporamide A, whereas bortezomib enhances T-L proteasome activity.
Initial results from early-stage clinical trials of salinosporamide A in relapsed/refractory multiple myeloma patients were presented at the 2011American Society of Hematology annual meeting.[12] Further early-stage trials of the drug in a number of different cancers are ongoing.[13]
Media related toSalinosporamides at Wikimedia Commons
