Salinosporamide A Explained

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.

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

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]

Notes and References

  1. Feling RH . Buchanan GO . Mincer TJ . Kauffman CA . Jensen PR . Fenical W . 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 . 2003 . 12548698 . 10.1002/anie.200390115. free .
  2. Chauhan D . A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib . Cancer Cell . 8 . 5 . 407–19 . 2005 . 16286248 . 10.1016/j.ccr.2005.10.013 . vanc. Catley L . Li G . 3 . Podar . Klaus . Hideshima . Teru . Velankar . Mugdha . Mitsiades . Constantine . Mitsiades . Nicolas . Yasui . Hiroshi. free .
  3. Web site: MDA-MB-435, and its derivation MDA-N, are Melanoma cell lines, not breast cancer cell lines. . 8 May 2015 . . . 6 January 2018.
  4. K. Lloyd, S. Glaser, B. Miller, Nereus Pharmaceuticals Inc.
  5. Beer LL . Moore BS . Biosynthetic convergence of salinosporamides A and B in the marine actinomycete Salinispora tropica . Org. Lett. . 9 . 5 . 845–8 . 2007 . 17274624 . 10.1021/ol063102o.
  6. Vaillancourt FH . Yeh E . Vosburg DA . Garneau-Tsodikova S . Sylvie Garneau-Tsodikova . Walsh CT . Nature's inventory of halogenation catalysts: oxidative strategies predominate . Chem. Rev. . 106 . 8 . 3364–78 . 2006 . 16895332 . 10.1021/cr050313i.
  7. Tsueng G . McArthur KA . Potts BC . Lam KS . Unique butyric acid incorporation patterns for salinosporamides A and B reveal distinct biosynthetic origins . Applied Microbiology and Biotechnology. 75. 5. 999–1005. 2007 . 17340108 . 10.1007/s00253-007-0899-7. 8992755 .
  8. Reddy LR . Saravanan P . Corey EJ . A simple stereocontrolled synthesis of salinosporamide A . J. Am. Chem. Soc. . 126 . 20 . 6230–1 . 2004 . 15149210 . 10.1021/ja048613p.
  9. Ling T . Macherla VR . Manam RR . McArthur KA . Potts BC . Enantioselective Total Synthesis of (−)-Salinosporamide A (NPI-0052) . Org. Lett. . 9 . 12 . 2289–92 . 2007 . 17497868 . 10.1021/ol0706051.
  10. Ma G . Nguyen H . Romo D . 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 . 2007 . 17477539 . 10.1021/ol070616u . 2518687.
  11. Endo A . Danishefsky SJ . Total synthesis of salinosporamide A . J. Am. Chem. Soc. . 127 . 23 . 8298–9 . 2005 . 15941259 . 10.1021/ja0522783.
  12. Web site: Marizomib May Be Effective In Relapsed/Refractory Multiple Myeloma (ASH 2011) . The Myeloma Beacon . 2012-01-23 . 2012-06-10.
  13. http://clinicaltrials.gov/ct2/results?term=marizomib&recr=Open&rslt=&type=&cond=&intr=&outc=&spons=&lead=&id=&state1=&cntry1=&state2=&cntry2=&state3=&cntry3=&locn=&gndr=&rcv_s=&rcv_e=&lup_s=&lup_e= ClinicalTrials.gov: Marizomib