Salinosporamide A

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Salinosporamide A
Other names (4R,5S)-4-(2-chloroethyl)-1-((1S)

-cyclohex-2-enyl(hydroxy)methyl) -5-methyl-6-oxa-2-azabicyclo 3.2.0heptane-3,7-dione
Properties
Molecular formula C15H20ClNO4
Molar mass 313.781 g/mol
Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)
Infobox disclaimer and references

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.[1][2] 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.

Contents

[edit] 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.[3] 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]

[edit] Mechanism of action

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

[edit] Biosynthesis

Salinosporamide A and B building Blocks
Salinosporamide A and B building Blocks
Proposed Biosynthesis of the Nonproteinogenic amino-acid beta-hydroxycyclohex-2'-enylanine (3) (R = H or S~PCP) via a Shunt in the Phenylalanine Biosynthetic Pathway
Proposed Biosynthesis of the Nonproteinogenic amino-acid beta-hydroxycyclohex-2'-enylanine (3) (R = H or S~PCP) via a Shunt in the Phenylalanine Biosynthetic Pathway
Biosynthesis
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 halogenase[4][5]. Recent work using 13C-labeled feeding experiments reveal distinct biosynthetic origins of salinosporamide A and B.[4][6]

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).

[edit] Total synthesis

First stereoselective sythesis was reported by Rajender Reddy and E. J.Corey. [7] Later several routes to the total synthesis of Salinosporamide A have been reported.[8][9][10][7]

[edit] 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.

[edit] References

  1. ^ a b Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W (2003). "Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora". Angew. Chem. Int. Ed. Engl. 42 (3): 355–7. doi:10.1002/anie.200390115. PMID 12548698. 
  2. ^ Chauhan D, Catley L, Li G, et al (2005). "A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib". Cancer Cell 8 (5): 407–19. doi:10.1016/j.ccr.2005.10.013. PMID 16286248. 
  3. ^ K. Lloyd, S. Glaser, B. Miller, Nereus Pharmaceuticals Inc.
  4. ^ a b Beer LL, Moore BS (2007). "Biosynthetic convergence of salinosporamides A and B in the marine actinomycete Salinispora tropica". Org. Lett. 9 (5): 845–8. doi:10.1021/ol063102o. PMID 17274624. 
  5. ^ Vaillancourt FH, Yeh E, Vosburg DA, Garneau-Tsodikova S, Walsh CT (2006). "Nature's inventory of halogenation catalysts: oxidative strategies predominate". Chem. Rev. 106 (8): 3364–78. doi:10.1021/cr050313i. PMID 16895332. 
  6. ^ Tsueng G, McArthur KA, Potts BC, Lam KS (2007). "Unique butyric acid incorporation patterns for salinosporamides A and B reveal distinct biosynthetic origins". doi:10.1007/s00253-007-0899-7. PMID 17340108. 
  7. ^ a b Reddy LR, Saravanan P, Corey EJ (2004). "A simple stereocontrolled synthesis of salinosporamide A". J. Am. Chem. Soc. 126 (20): 6230–1. doi:10.1021/ja048613p. PMID 15149210. 
  8. ^ Ling T, Macherla VR, Manam RR, McArthur KA, Potts BC (2007). "Enantioselective Total Synthesis of (-)-Salinosporamide A (NPI-0052)". Org. Lett. 9 (12): 2289–92. doi:10.1021/ol0706051. PMID 17497868. 
  9. ^ Ma G, Nguyen H, Romo D (2007). "Concise total synthesis of (+/-)-salinosporamide A, (+/-)-cinnabaramide A, and derivatives via a bis-cyclization process: implications for a biosynthetic pathway?". Org. Lett. 9 (11): 2143–6. doi:10.1021/ol070616u. PMID 17477539. 
  10. ^ Endo A, Danishefsky SJ (2005). "Total synthesis of salinosporamide A". J. Am. Chem. Soc. 127 (23): 8298–9. doi:10.1021/ja0522783. PMID 15941259.