Salinosporamide A

Salinosporamide A (Marizomib) is a potent proteasome inhibitor being studied as a potential anticancer agent. It entered phase I human clinical trials for the treatment of multiple myeloma, only three years after its discovery in 2003.[1][2] This marine natural product is produced by the obligate marine bacteria Salinispora tropica and Salinispora arenicola, which are found in ocean sediment. Salinosporamide A belongs to a family of compounds, known collectively as salinosporamides, which possess a densely functionalized γ-lactam-β-lactone bicyclic core.

Salinosporamide A
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
KEGG
UNII
  • InChI=1S/C15H20ClNO4/c1-14-10(7-8-16)12(19)17-15(14,13(20)21-14)11(18)9-5-3-2-4-6-9/h3,5,9-11,18H,2,4,6-8H2,1H3,(H,17,19)/t9-,10+,11+,14+,15+/m1/s1 ☒N
    Key: NGWSFRIPKNWYAO-SHTIJGAHSA-N ☒N
  • InChI=1/C15H20ClNO4/c1-14-10(7-8-16)12(19)17-15(14,13(20)21-14)11(18)9-5-3-2-4-6-9/h3,5,9-11,18H,2,4,6-8H2,1H3,(H,17,19)/t9-,10+,11+,14+,15+/m1/s1
    Key: NGWSFRIPKNWYAO-SHTIJGAHBB
  • O=C1O[C@@]3(C)[C@H](C(=O)N[C@@]13[C@@H](O)[C@@H]2/C=C\CCC2)CCCl
  • C[C@]13OC(=O)C3(NC(=O)[C@@H]1CCCl)[C@@H](O)C2/C=C\CCC2
Properties
C15H20ClNO4
Molar mass 313.781 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)
Infobox references

History

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 cultured Salinispora 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 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 brain tumor, SK-MEL-28 melanoma, and MDA-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]

Mechanism of action

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

Biosynthesis
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
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.[5][6] Recent work using 13C-labeled feeding experiments reveal distinct biosynthetic origins of salinosporamide A and B.[5][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

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]

Clinical study

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.

Initial results from early-stage clinical trials of salinosporamide A in relapsed/refractory multiple myeloma patients were presented at the 2011 American Society of Hematology annual meeting.[12] Further early-stage trials of the drug in a number of different cancers are ongoing.[13]

References
  1. 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. "MDA-MB-435, and its derivation MDA-N, are Melanoma cell lines, not breast cancer cell lines". Developmental Therapeutics Program. National Cancer Institute. 8 May 2015. Retrieved 6 January 2018.
  4. K. Lloyd, S. Glaser, B. Miller, Nereus Pharmaceuticals Inc.
  5. 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.
  6. 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.
  7. Tsueng G; McArthur KA; Potts BC; Lam KS (2007). "Unique butyric acid incorporation patterns for salinosporamides A and B reveal distinct biosynthetic origins". Applied Microbiology and Biotechnology. 75 (5): 999–1005. doi:10.1007/s00253-007-0899-7. PMID 17340108. S2CID 8992755.
  8. 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.
  9. 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.
  10. 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. PMC 2518687. PMID 17477539.
  11. Endo A; Danishefsky SJ (2005). "Total synthesis of salinosporamide A". J. Am. Chem. Soc. 127 (23): 8298–9. doi:10.1021/ja0522783. PMID 15941259.
  12. "Marizomib May Be Effective In Relapsed/Refractory Multiple Myeloma (ASH 2011)". The Myeloma Beacon. 2012-01-23. Retrieved 2012-06-10.
  13. ClinicalTrials.gov: Marizomib
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