SILVESTROL

Silvestrol
Identifiers
	IUPAC name Methyl (1R,2R,3S,3aR,8bS)-6-[[(2S,3R,6R)-6-[(1R)-1,2-dihydroxyethyl]-3-methoxy-1,4-dioxan-2-yl]oxy]-1,8b-dihydroxy-8-methoxy-3a-(4-methoxyphenyl)-3-phenyl-2,3-dihydro-1H-cyclopenta[b] [1]benzofuran-2-carboxylate;
CAS Number	697235-38-4 ;
PubChem CID	11787114;
ChemSpider	9961792;
UNII	KK3Y3KN5BV;
ChEBI	CHEBI:66484;
ChEMBL	ChEMBL555196;
Chemical and physical data
Formula	C34H38O13
Molar mass	654.665 g·mol−1
3D model ( JSmol)	Interactive image;
	SMILES CO[C@H]1[C@@H](O[C@H](CO1)[C@@H](CO)O)OC2=CC3=C(C(=C2)OC)[C@@]4([C@@H]([C@@H]([C@H]([C@@]4(O3)C5=CC=C(C=C5)OC)C6=CC=CC=C6)C(=O)OC)O)O;
	InChI InChI=1S/C34H38O13/c1-40-20-12-10-19(11-13-20)34-27(18-8-6-5-7-9-18)26(30(38)42-3)29(37)33(34,39)28-23(41-2)14-21(15-24(28)47-34)45-32-31(43-4)44-17-25(46-32)22(36)16-35/h5-15,22,25-27,29,31-32,35-37,39H,16-17H2,1-4H3/t22-,25-,26-,27-,29-,31-,32-,33+,34+/m1/s1; Key:GVKXFVCXBFGBCD-QKDMMWSPSA-N;

Silvestrol is a natural product from the flavagline family, with a cyclopenta[b] benzofuran core structure and an unusual dioxane ether side chain, which is found in the bark of trees from the genus Aglaia, especially Aglaia silvestris and Aglaia foveolata.^[1]

Bioactivity

It acts as a potent and selective inhibitor of the RNA helicase enzyme eIF4A, and has both broad-spectrum antiviral activity against diseases such as Ebola and coronaviruses, ^[2]^[3]^[4]^[5]^[6] and anti-cancer properties,^[7]^[8] which makes it of considerable interest in medical research. However, as it cannot be extracted from tree bark in commercial amounts and is prohibitively complex to produce synthetically,^[9] practical applications have focused more on structurally simplified analogues such as CR-31-B.^[10]

References

^ Pan L, Woodard JL, Lucas DM, Fuchs JR, Kinghorn AD (July 2014). "Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species". Natural Product Reports. 31 (7): 924–39. doi: 10.1039/c4np00006d. PMC 4091845. PMID 24788392.
^ Biedenkopf N, Lange-Grünweller K, Schulte FW, Weißer A, Müller C, Becker D, et al. (January 2017). "The natural compound silvestrol is a potent inhibitor of Ebola virus replication". Antiviral Research. 137: 76–81. doi: 10.1016/j.antiviral.2016.11.011. PMID 27864075. S2CID 205577158.
^ Elgner F, Sabino C, Basic M, Ploen D, Grünweller A, Hildt E (March 2018). "Inhibition of Zika Virus Replication by Silvestrol". Viruses. 10 (4): 149. doi: 10.3390/v10040149. PMC 5923443. PMID 29584632.
^ Müller C, Schulte FW, Lange-Grünweller K, Obermann W, Madhugiri R, Pleschka S, et al. (February 2018). "Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses". Antiviral Research. 150: 123–129. doi: 10.1016/j.antiviral.2017.12.010. PMC 7113723. PMID 29258862.
^ Henss L, Scholz T, Grünweller A, Schnierle BS (October 2018). "Silvestrol Inhibits Chikungunya Virus Replication". Viruses. 10 (11): 592. doi: 10.3390/v10110592. PMC 6266838. PMID 30380742.
^ Pillaiyar T, Meenakshisundaram S, Manickam M (April 2020). "Recent discovery and development of inhibitors targeting coronaviruses". Drug Discovery Today. 25 (4): 668–688. doi: 10.1016/j.drudis.2020.01.015. PMC 7102522. PMID 32006468.
^ Kogure T, Kinghorn AD, Yan I, Bolon B, Lucas DM, Grever MR, Patel T (2013). "Therapeutic potential of the translation inhibitor silvestrol in hepatocellular cancer". PLOS ONE. 8 (9): e76136. Bibcode: 2013PLoSO...876136K. doi: 10.1371/journal.pone.0076136. PMC 3784426. PMID 24086701.
^ Pelletier J, Graff J, Ruggero D, Sonenberg N (January 2015). "Targeting the eIF4F translation initiation complex: a critical nexus for cancer development". Cancer Research. 75 (2): 250–63. doi: 10.1158/0008-5472.CAN-14-2789. PMC 4299928. PMID 25593033.
^ El Sous M, Khoo ML, Holloway G, Owen D, Scammells PJ, Rizzacasa MA (2007). "Total synthesis of (-)-episilvestrol and (-)-silvestrol". Angewandte Chemie. 46 (41): 7835–8. doi: 10.1002/anie.200702700. PMID 17823902.
^ Müller C, Obermann W, Schulte FW, Lange-Grünweller K, Oestereich L, Elgner F, et al. (January 2020). "Comparison of broad-spectrum antiviral activities of the synthetic rocaglate CR-31-B (-) and the eIF4A-inhibitor Silvestrol". Antiviral Research. 175: 104706. doi: 10.1016/j.antiviral.2020.104706. PMC 7114339. PMID 31931103.

[pmid24788392-1] Pan L, Woodard JL, Lucas DM, Fuchs JR, Kinghorn AD (July 2014). "Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species". Natural Product Reports. 31 (7): 924–39. doi: 10.1039/c4np00006d. PMC 4091845. PMID 24788392.

[2] Biedenkopf N, Lange-Grünweller K, Schulte FW, Weißer A, Müller C, Becker D, et al. (January 2017). "The natural compound silvestrol is a potent inhibitor of Ebola virus replication". Antiviral Research. 137: 76–81. doi: 10.1016/j.antiviral.2016.11.011. PMID 27864075. S2CID 205577158.

[3] Elgner F, Sabino C, Basic M, Ploen D, Grünweller A, Hildt E (March 2018). "Inhibition of Zika Virus Replication by Silvestrol". Viruses. 10 (4): 149. doi: 10.3390/v10040149. PMC 5923443. PMID 29584632.

[4] Müller C, Schulte FW, Lange-Grünweller K, Obermann W, Madhugiri R, Pleschka S, et al. (February 2018). "Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses". Antiviral Research. 150: 123–129. doi: 10.1016/j.antiviral.2017.12.010. PMC 7113723. PMID 29258862.

[5] Henss L, Scholz T, Grünweller A, Schnierle BS (October 2018). "Silvestrol Inhibits Chikungunya Virus Replication". Viruses. 10 (11): 592. doi: 10.3390/v10110592. PMC 6266838. PMID 30380742.

[pmid32006468-6] Pillaiyar T, Meenakshisundaram S, Manickam M (April 2020). "Recent discovery and development of inhibitors targeting coronaviruses". Drug Discovery Today. 25 (4): 668–688. doi: 10.1016/j.drudis.2020.01.015. PMC 7102522. PMID 32006468.

[7] Kogure T, Kinghorn AD, Yan I, Bolon B, Lucas DM, Grever MR, Patel T (2013). "Therapeutic potential of the translation inhibitor silvestrol in hepatocellular cancer". PLOS ONE. 8 (9): e76136. Bibcode: 2013PLoSO...876136K. doi: 10.1371/journal.pone.0076136. PMC 3784426. PMID 24086701.

[8] Pelletier J, Graff J, Ruggero D, Sonenberg N (January 2015). "Targeting the eIF4F translation initiation complex: a critical nexus for cancer development". Cancer Research. 75 (2): 250–63. doi: 10.1158/0008-5472.CAN-14-2789. PMC 4299928. PMID 25593033.

[9] El Sous M, Khoo ML, Holloway G, Owen D, Scammells PJ, Rizzacasa MA (2007). "Total synthesis of (-)-episilvestrol and (-)-silvestrol". Angewandte Chemie. 46 (41): 7835–8. doi: 10.1002/anie.200702700. PMID 17823902.

[10] Müller C, Obermann W, Schulte FW, Lange-Grünweller K, Oestereich L, Elgner F, et al. (January 2020). "Comparison of broad-spectrum antiviral activities of the synthetic rocaglate CR-31-B (-) and the eIF4A-inhibitor Silvestrol". Antiviral Research. 175: 104706. doi: 10.1016/j.antiviral.2020.104706. PMC 7114339. PMID 31931103.

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Bioactivity

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Bioactivity

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Identifiers

IUPAC name Methyl (1R,2R,3S,3aR,8bS)-6-[[(2S,3R,6R)-6-[(1R)-1,2-dihydroxyethyl]-3-methoxy-1,4-dioxan-2-yl]oxy]-1,8b-dihydroxy-8-methoxy-3a-(4-methoxyphenyl)-3-phenyl-2,3-dihydro-1H-cyclopenta[b] [1]benzofuran-2-carboxylate
CAS Number	697235-38-4^Y
PubChem CID	11787114
ChemSpider	9961792
UNII	KK3Y3KN5BV
ChEBI	CHEBI:66484
ChEMBL	ChEMBL555196
Chemical and physical data
Formula	C₃₄H₃₈O₁₃
Molar mass	654.665 g·mol⁻¹
3D model ( JSmol)	Interactive image
SMILES CO[C@H]1[C@@H](O[C@H](CO1)[C@@H](CO)O)OC2=CC3=C(C(=C2)OC)[C@@]4([C@@H]([C@@H]([C@H]([C@@]4(O3)C5=CC=C(C=C5)OC)C6=CC=CC=C6)C(=O)OC)O)O
InChI InChI=1S/C34H38O13/c1-40-20-12-10-19(11-13-20)34-27(18-8-6-5-7-9-18)26(30(38)42-3)29(37)33(34,39)28-23(41-2)14-21(15-24(28)47-34)45-32-31(43-4)44-17-25(46-32)22(36)16-35/h5-15,22,25-27,29,31-32,35-37,39H,16-17H2,1-4H3/t22-,25-,26-,27-,29-,31-,32-,33+,34+/m1/s1 Key:GVKXFVCXBFGBCD-QKDMMWSPSA-N