Silvestrol

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Structural formula
Structural formula of Silvestrol
General
Surname Silvestrol
other names
  • Methyl- (1 R , 2 R , 3 S , 3a R , 8b S ) -6 - {[(3 R , 6 R ) -6 - [(1 R ) -1,2-dihydroxyethyl] -3-methoxy- 1,4-dioxan-2-yl] oxy} -1,8b-dihydroxy-8-methoxy-3a- (4-methoxyphenyl) -3-phenyl-2,3-dihydro-1 H -cyclopenta [ b ] benzofuran 2-carboxylate
  • (-) - Silvestrol
Molecular formula C 34 H 38 O 13
External identifiers / databases
CAS number 697235-38-4
PubChem 11787114
ChemSpider 9961792
Wikidata Q27135085
Drug information
Mechanism of action

eIF4A inhibitor

properties
Molar mass 654.66 g · mol -1
density

1.45 g cm −3

Melting point

120-122 ° C

safety instructions
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Silvestrol is a natural product from the cyclopenta [ b ] benzofurane group .

Occurrence

Silvestrol and various derivatives can be prepared from fruit and twigs of the tropical plant Aglaia foveolata and related species extracts are. The genus Aglaia belongs to the mahogany family ("Meliaceae"), which are mainly endemic to Indonesia and Malaysia .

properties

Silvestrol is a specific and potent inhibitor of RNA helicase eIF4A , an enzyme which in the initiation of translation (as part of the protein biosynthesis is involved) and RNA secondary structures in messenger RNAs (mRNAs) with cap structure unwinds. This enables the small ribosomal subunit to dock on the mRNA. In particular, some mRNAs from proto-oncogenes and viral mRNAs require the helicase activity of eIF4A for their protein biosynthesis.

Applications

In preclinical cancer research, Silvestrol has been used for several years to inhibit tumor cell growth in human cell cultures and in tumor mouse models. Silvestrol shows low cytotoxicity compared to healthy cells.

In a recent study with Ebola -infected human cells it was shown that Silvestrol can effectively reduce the viral load and the production of viral proteins is greatly reduced in primary human macrophages and in the Huh-7 cell line (isolated from human liver carcinoma ). There could also be similar activity against the Chikungunya virus , the Zika virus and against picorna and coronaviruses .  

Studies with human blood cells showed an immunomodulatory influence by Silvestrol on isolated macrophages and dendritic cells.

The natural substance has not yet been approved for use on humans. In addition, there are currently (as of 2016) no clinical studies with Silvestrol.

Manufacturing

In 2007 the total synthesis of Silvestrol succeeded for the first time .

Individual evidence

  1. ↑ a b Entry on Silvestrol 697235-38-4 at ChemBlink , accessed on December 20, 2016.
  2. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  3. ↑ a b L. Pan, JL Woodard, DM Lucas, JR Fuchs, AD Kinghorn: Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species. In: Natural product reports. Volume 31, number 7, July 2014, pp. 924-939, doi: 10.1039 / c4np00006d , PMID 24788392 , PMC 4091845 (free full text).
  4. ↑ C. Lu, L. Makala, D. Wu, Y. Cai: Targeting translation: eIF4E as an emerging anticancer drug target. In: Expert reviews in molecular medicine. Volume 18, January 2016, p. E2, doi: 10.1017 / erm.2015.20 , PMID 26775675 .
  5. ↑ Jerry Pelletier, Jeremy Graff, Davide Ruggero, Nahum Sonenberg: Targeting the eIF4F Translation Initiation Complex: A Critical Nexus for Cancer Development . In: Cancer Research . tape 75 , no. 2 , 2015, p. 250-263 , doi : 10.1158 / 0008-5472.can-14-2789 .
  6. ↑ Takayuki Kogure, A. Douglas Kinghorn, Irene Yan, Brad Bolon, David M. Lucas: Therapeutic Potential of the Translation Inhibitor Silvestrol in Hepatocellular Cancer . In: PLOS ONE . tape 8 , no. 9 , 2013, p. e76136 , doi : 10.1371 / journal.pone.0076136 , PMID 24086701 , PMC 3784426 (free full text).
  7. ↑ WL Chen, L. Pan, AD Kinghorn, SM Swanson, JE Burdette: Silvestrol induces early autophagy and apoptosis in human melanoma cells. In: BMC Cancer . Volume 16, January 2016, p. 17, doi: 10.1186 / s12885-015-1988-0 , PMID 26762417 , PMC 4712514 (free full text).
  8. ↑ Kogure T, Kinghorn AD, Yan I, Bolon B, Lucas DM, Grever MR, Patel T: Therapeutic potential of the translation inhibitor silvestrol in hepatocellular cancer . In: PLOS ONE . 8, No. 9, 2013, p. E76136. bibcode : 2013PLoSO ... 876136K . doi : 10.1371 / journal.pone.0076136 . PMID 24086701 . PMC 3784426 (free full text).
  9. ↑ Pelletier J, Graff J, Ruggero D, Sonenberg N: Targeting the eIF4F translation initiation complex: a critical nexus for cancer development . In: Cancer Research . 75, No. 2, January 2015, pp. 250-63. doi : 10.1158 / 0008-5472.CAN-14-2789 . PMID 25593033 . PMC 4299928 (free full text).
  10. ↑ Nadine Biedenkopf, Kerstin Lange-Grünweller, Falk W. Schulte, Aileen Weißer, Christin Müller: The natural compound silvestrol is a potent inhibitor of Ebola virus replication . In: Antiviral Research . tape 137 , 2017, p. 76-81 , doi : 10.1016 / j.antiviral.2016.11.011 .
  11. ↑ Henss L, Scholz T, Grünweller A, Schnierle BS: Silvestrol Inhibits Chikungunya Virus Replication . In: Viruses . 10, No. 11, October 2018, p. 592. doi : 10.3390 / v10110592 . PMID 30380742 . PMC 6266838 (free full text).
  12. ↑ Elgner F, Sabino C, Basic M, Ploen D, Grünweller A, Hildt E: Inhibition of Zika Virus Replication by Silvestrol . In: Viruses . 10, No. 4, March 2018, p. 149. doi : 10.3390 / v10040149 . PMID 29584632 . PMC 5923443 (free full text).
  13. ↑ a b Müller C, Schulte FW, Lange-Grünweller K, Obermann W, Madhugiri R, Pleschka S, Ziebuhr J, Hartmann RK, Grünweller A: Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona and picornaviruses . In: Antiviral Research . 150, February 2018, pp. 123–129. doi : 10.1016 / j.antiviral.2017.12.010 . PMID 29258862 .
  14. ↑ Pillaiyar T, Meenakshisundaram S, Manickam M. Recent discovery and development of inhibitors targeting coronaviruses. Drug Discov Today . 2020 Jan 30. pii: S1359-6446 (20) 30041-6. doi : 10.1016 / j.drudis.2020.01.015 . PMID 32006468
  15. ↑ Daniale Albat: New Virus Inhibitor from the Sea , on scinexx.de from March 27, 2020
  16. ↑ Leonard Blum, Gerd Geisslinger, Michael J. Parnham, Arnold Grünweller, Susanne Schiffmann: Natural antiviral compound silvestrol modulates human monocyte-derived macrophages and dendritic cells . In: Journal of Cellular and Molecular Medicine . ISSN  1582-4934 , doi : 10.1111 / jcmm.15360 .
  17. ↑ Silvestrol at clinicaltrials.gov, accessed on July 21, 2019.
  18. ↑ B. Gerard, R. Cencic et al : Enantioselective synthesis of the complex rocaglate (-) - silvestrol. In: Angewandte Chemie. Volume 46, number 41, 2007, pp. 7831-7834, doi: 10.1002 / anie.200702707 . PMID 17806093 .
  19. ↑ M. El Sous, ML Khoo et al : Total synthesis of (-) - episilvestrol and (-) - silvestrol. In: Angewandte Chemie. Volume 46, number 41, 2007, pp. 7835-7838, doi: 10.1002 / anie.200702700 . PMID 17823902 .