Salinosporamide A

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OtherNames = (4R,5S)-4-(2-chloroethyl)-1-((1S)-cyclohex-2-enyl(hydroxy)methyl)-5-methyl-6-oxa-2-azabicyclo3.2.0heptane-3,7-dione
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Formula = C₁₅H₂₀ClNO₄
MolarMass = 313.781 g/mol
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Salinosporamide A is a potent proteasome inhibitor used as an anticancer agent that recently entered phase I human clinical trials for the treatment of multiple myeloma only three years after its discovery.cite journal |author=Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W |title=Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora |journal=Angew. Chem. Int. Ed. Engl. |volume=42 |issue=3 |pages=355–7 |year=2003 |pmid=12548698 |doi=10.1002/anie.200390115] cite journal |author=Chauhan D, Catley L, Li G, "et al" |title=A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib |journal=Cancer Cell |volume=8 |issue=5 |pages=407–19 |year=2005 |pmid=16286248 |doi=10.1016/j.ccr.2005.10.013] This novel marine natural product is produced by the recently described obligate marine bacterium "Salinispora tropica" which is found in ocean sediment. Salinosporamide A belongs to a family of compounds possessing a densely functionalized γ-lactam-β-lactone bicycle.

History

In preliminary screening, a high percentage of the organic extracts of cultured Salinospora strains possessed antibiotic and anticancer activities, which suggests that these bacteria are an excellent resource for drug discovery. Salinospora 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 with omuralide, it is uniquely functionalized. Salinosporamide A displayed potent in vitro cytotoxicity against HCT-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's 60-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 against NCI-H226 non-small cell lung cancer, SF-539 CNS cancer, SK-MEL-28 melanoma, and MDA-MB-435 breast cancer (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. [K. Lloyd, S. Glaser, B. Miller, Nereus Pharmaceuticals Inc.] 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.cite journal |author=Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W |title=Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora |journal=Angew. Chem. Int. Ed. Engl. |volume=42 |issue=3 |pages=355–7 |year=2003 |pmid=12548698 |doi=10.1002/anie.200390115]

Mechanism of action

Salinosporamide A inhibits proteasome activity by covalently modifying the active site threonine residues of the 20S proteasome.

Biosynthesis

It was originally hypothesized that Salinosporamide B was a biosynthetic precursor to Salinosporamide A due to their structural similarities.

It was thought that the halogenation of the unactivated methyl group was catalyzed by a non-heme iron halogenasecite journal |author=Beer LL, Moore BS |title=Biosynthetic convergence of salinosporamides A and B in the marine actinomycete Salinispora tropica |journal=Org. Lett. |volume=9 |issue=5 |pages=845–8 |year=2007 |pmid=17274624 |doi=10.1021/ol063102o] cite journal |author=Vaillancourt FH, Yeh E, Vosburg DA, Garneau-Tsodikova S, Walsh CT |title=Nature's inventory of halogenation catalysts: oxidative strategies predominate |journal=Chem. Rev. |volume=106 |issue=8 |pages=3364–78 |year=2006 |pmid=16895332 |doi=10.1021/cr050313i] . Recent work using ¹³C-labeled feeding experiments reveal distinct biosynthetic origins of salinosporamide A and B.cite journal |author=Beer LL, Moore BS |title=Biosynthetic convergence of salinosporamides A and B in the marine actinomycete Salinispora tropica |journal=Org. Lett. |volume=9 |issue=5 |pages=845–8 |year=2007 |pmid=17274624 |doi=10.1021/ol063102o] cite journal |author=Tsueng G, McArthur KA, Potts BC, Lam KS |title=Unique butyric acid incorporation patterns for salinosporamides A and B reveal distinct biosynthetic origins |journal= |volume= |issue= |pages= |year=2007 |pmid=17340108 |doi=10.1007/s00253-007-0899-7]

While they share the biosynthetic precursors acetate 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 the halogen atom. A hybrid polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) pathway is most likely the biosynthetic mechanism in which acetyl-CoA and butyrate-derived ethylmalonyl-CoA condense to yield the β-ketothioester (4), which then reacts with (3) to generate the linear precursor (5).

Total synthesis

First stereoselective synthesis was reported by Rajender Reddy and E. J.Corey. cite journal |author=Reddy LR, Saravanan P, Corey EJ |title=A simple stereocontrolled synthesis of salinosporamide A |journal=J. Am. Chem. Soc. |volume=126 |issue=20 |pages=6230–1 |year=2004 |pmid=15149210 |doi=10.1021/ja048613p] Later several routes to the total synthesis of Salinosporamide A have been reported.cite journal |author=Ling T, Macherla VR, Manam RR, McArthur KA, Potts BC |title=Enantioselective Total Synthesis of (-)-Salinosporamide A (NPI-0052) |journal=Org. Lett. |volume=9 |issue=12 |pages=2289–92 |year=2007 |pmid=17497868 |doi=10.1021/ol0706051] cite journal |author=Ma G, Nguyen H, Romo D |title=Concise total synthesis of (+/-)-salinosporamide A, (+/-)-cinnabaramide A, and derivatives via a bis-cyclization process: implications for a biosynthetic pathway? |journal=Org. Lett. |volume=9 |issue=11 |pages=2143–6 |year=2007 |pmid=17477539 |doi=10.1021/ol070616u] cite journal |author=Endo A, Danishefsky SJ |title=Total synthesis of salinosporamide A |journal=J. Am. Chem. Soc. |volume=127 |issue=23 |pages=8298–9 |year=2005 |pmid=15941259 |doi=10.1021/ja0522783] cite journal |author=Reddy LR, Saravanan P, Corey EJ |title=A simple stereocontrolled synthesis of salinosporamide A |journal=J. Am. Chem. Soc. |volume=126 |issue=20 |pages=6230–1 |year=2004 |pmid=15149210 |doi=10.1021/ja048613p]

Clinical use

"In vitro" studies using purified 20S proteasomes showed that Salinosporamide A has lower EC50 for trypsin-like (T-L) activity than does Bortezomib. In vivo animal model studies show marked inhibition of T-L activity in response to Salinosporamide A, whereas Bortezomib enhances T-L proteasome activity.

References