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 actionedit
Salinosporamide A inhibits proteasome activity by covalently modifying the active site threonine residues of the 20S proteasome.[citation needed]
Biosynthesisedit
Salinosporamide A and B building blocksProposed biosynthesis of the nonproteinogenic amino-acid beta-hydroxycyclohex-2'-enylanine (3) (R = H or S~PCP) via a shunt in the phenylalanine biosynthetic pathwayBiosynthesis
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 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 synthesisedit
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 studyedit
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]
Referencesedit
^ abFeling 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.
^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.
^K. Lloyd, S. Glaser, B. Miller, Nereus Pharmaceuticals Inc.
^ abBeer 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.
^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.
^ abReddy 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.
^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.
^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. PMC2518687. PMID 17477539.
^Endo A; Danishefsky SJ (2005). "Total synthesis of salinosporamide A". J. Am. Chem. Soc. 127 (23): 8298–9. doi:10.1021/ja0522783. PMID 15941259.
^"Marizomib May Be Effective In Relapsed/Refractory Multiple Myeloma (ASH 2011)". The Myeloma Beacon. 2012-01-23. Retrieved 2012-06-10.
Media related to Salinosporamides at Wikimedia Commons
April 13, 2024
salinosporamide, marizomib, potent, proteasome, inhibitor, being, studied, potential, anticancer, agent, entered, phase, human, clinical, trials, treatment, multiple, myeloma, only, three, years, after, discovery, 2003, this, marine, natural, product, produced. 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 g lactam b lactone bicyclic core Salinosporamide A NamesPreferred 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 dioneOther names Marizomib NPI 0052IdentifiersCAS Number 437742 34 2 N3D model JSmol Interactive imageInteractive imageChEBI CHEBI 48045 NChEMBL ChEMBL371405 NChemSpider 9522473 NKEGG D09640PubChem CID 11347535UNII 703P9YDP7F YCompTox Dashboard EPA DTXSID00904019InChI 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 NKey NGWSFRIPKNWYAO SHTIJGAHSA N NInChI 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 s1Key NGWSFRIPKNWYAO SHTIJGAHBBSMILES O C1O C 3 C C H C O N C 13 C H O C H 2 C C CCC2 CCClC C 13OC O C3 NC O C H 1CCCl C H O C2 C C CCC2PropertiesChemical formula C15H20ClNO4Molar mass 313 781 g molExcept where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa N verify what is Y N Infobox references Contents 1 History 2 Mechanism of action 3 Biosynthesis 4 Total synthesis 5 Clinical study 6 References 7 External linksHistory editSalinosporamide 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 editSalinosporamide A inhibits proteasome activity by covalently modifying the active site threonine residues of the 20S proteasome citation needed Biosynthesis edit nbsp Salinosporamide A and B building blocks nbsp 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 nbsp BiosynthesisIt 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 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 b 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 b ketothioester 4 which then reacts with 3 to generate the linear precursor 5 Total synthesis editThe 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 editIn 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 edit 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 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 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 K Lloyd S Glaser B Miller Nereus Pharmaceuticals Inc 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 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 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 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 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 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 Endo A Danishefsky SJ 2005 Total synthesis of salinosporamide A J Am Chem Soc 127 23 8298 9 doi 10 1021 ja0522783 PMID 15941259 Marizomib May Be Effective In Relapsed Refractory Multiple Myeloma ASH 2011 The Myeloma Beacon 2012 01 23 Retrieved 2012 06 10 ClinicalTrials gov MarizomibExternal links edit nbsp Media related to Salinosporamides at Wikimedia Commons Retrieved from https en wikipedia org w index php title Salinosporamide A amp oldid 1186743755, wikipedia, wiki, book, books, library,
