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2000
Volume 2, Issue 2
  • ISSN: 2666-0016
  • E-ISSN: 2666-0008

Abstract

Flavaglines, a family of compounds from plants used in traditional Chinese medicine, exhibit a broad range of biological effects, including anticancer, antiviral, cardioprotective, and anti-inflammatory activities. They exert their action by targeting the scaffold proteins called prohibitin-1 and -2 and the mRNA helicases eIF4A and DDX3. Flavaglines are densely functionalized cyclopenta[]benzofurans that have attracted the attention of some of the most eminent organic chemists. This review provides an overview of the biosynthesis, total synthesis, and pharmacological activities of flavaglines, which have recently culminated with the entrance of a synthetic derivative, Zotatifin, into clinical trials against advanced refractory solid tumors, intolerant to standard treatments.

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2022-01-18
2025-03-15
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References

  1. HarnetiD. SupratmanU. Phytochemistry and biological activities of Aglaia species.Phytochemistry2021181, 112540.10.1016/j.phytochem.2020.11254033130371
    [Google Scholar]
  2. HeyneK. The Useful Indonesian Plants; Research and Development Agency.Jakarta, IndonesiaMinistry of Forestry198710291045
    [Google Scholar]
  3. LemmensR.H.M.J. SoerianegaraI. WongW.C. Plant Resources of South-East Asia. No. 5(2): Timber trees: Minor commercial timbers.LeidenBackhuys Publishers1995
    [Google Scholar]
  4. JanakiS. VijayasekaranV. ViswanathanS. BalakrishnaK. Anti-inflammatory activity of Aglaia roxburghiana var. beddomei extract and triterpenes roxburghiadiol A and B.J. Ethnopharmacol.1999671455110.1016/S0378‑8741(99)00063‑X10616959
    [Google Scholar]
  5. AyyanarM. IgnacimuthuS. Traditional knowledge of Kani tribals in Kouthalai of Tirunelveli hills, Tamil Nadu, India.J. Ethnopharmacol.2005102224625510.1016/j.jep.2005.06.02016054791
    [Google Scholar]
  6. KhareC.P. Indian Herbal Remedies.Berlin, HeidelbergSpringer-Verlag200410.1007/978‑3‑642‑18659‑2
    [Google Scholar]
  7. DivisionM.R. Traditional medicine textbook (Thai drug).BangkokOffice of the Permanent Secretary for Public Health, Ministry of Public Health1998
    [Google Scholar]
  8. KingM.L. ChiangC.C. LingH.C. FujitaE. OchiaiM. McPhailA.T. X-ray crystal structure of rocaglamide, a novel antileukemic 1H-cyclopenta[b]benzofuran from Aglaia elliptifolia.J. Chem. Soc. Chem. Commun.1982201150115110.1039/c39820001150
    [Google Scholar]
  9. GregerH. Comparative phytochemistry of flavaglines (=rocaglamides), a group of highly bioactive flavolignans from Aglaia species (Meliaceae).Phytochem. Rev.202114010.1007/s11101‑021‑09761‑534104125
    [Google Scholar]
  10. YangH.J. LiY.N. YanC. YangJ. ZengY.R. YiP. LiY.M. HaoX.J. YuanC.M. Discovery and synthesis of rocaglaol derivatives inducing apoptosis in HCT116 cells via suppression of MAPK signaling pathway.Fitoterapia2021151, 104876.10.1016/j.fitote.2021.10487633675885
    [Google Scholar]
  11. SchulzG. VictoriaC. KirschningA. SteinmannE. Rocaglamide and silvestrol: A long story from anti-tumor to anti-coronavirus compounds.Nat. Prod. Rep.2021381182310.1039/D0NP00024H32699874
    [Google Scholar]
  12. PanL. WoodardJ.L. LucasD.M. FuchsJ.R. KinghornA.D. Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species.Nat. Prod. Rep.201431792493910.1039/C4NP00006D24788392
    [Google Scholar]
  13. HausottB. GregerH. MarianB. Flavaglines: A group of efficient growth inhibitors block cell cycle progression and induce apoptosis in colorectal cancer cells.Int. J. Cancer2004109693394010.1002/ijc.2003315027128
    [Google Scholar]
  14. BordeleauM-E. RobertF. GerardB. LindqvistL. ChenS.M.H. WendelH-G. BremB. GregerH. LoweS.W. PorcoJ.A.Jr PelletierJ. Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model.J. Clin. Invest.200811872651266010.1172/JCI3475318551192
    [Google Scholar]
  15. CencicR. CarrierM. Galicia-VázquezG. BordeleauM.E. SukariehR. BourdeauA. BremB. TeodoroJ.G. GregerH. TremblayM.L. PorcoJ.A.Jr PelletierJ. Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol.PLoS One200944, e5223.10.1371/journal.pone.000522319401772
    [Google Scholar]
  16. ChambersJ.M. LindqvistL.M. WebbA. HuangDCS. SavageGP. RizzacasaM.A. Synthesis of biotinylated Episilvestrol: Highly selective targeting of the translation factors eIF4AI/II.Org. Lett.201315614061409
    [Google Scholar]
  17. SadlishH. Galicia-VazquezG. ParisC.G. AustT. BhullarB. ChangL. HelliwellS.B. HoepfnerD. KnappB. RiedlR. RoggoS. SchuiererS. StuderC. PorcoJ.A.Jr PelletierJ. MovvaN.R. Evidence for a functionally relevant rocaglamide binding site on the eIF4A-RNA complex.ACS Chem. Biol.2013871519152710.1021/cb400158t23614532
    [Google Scholar]
  18. PolierG. NeumannJ. ThuaudF. RibeiroN. GelhausC. SchmidtH. GiaisiM. KöhlerR. MüllerW.W. ProkschP. LeippeM. JanssenO. DésaubryL. KrammerP.H. Li-WeberM. The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2.Chem. Biol.20121991093110410.1016/j.chembiol.2012.07.01222999878
    [Google Scholar]
  19. ErnstJ.T. ThompsonP.A. NilewskiC. SprengelerP.A. SperryS. PackardG. MichelsT. XiangA. TranC. WegerskiC.J. EamB. YoungN.P. FishS. ChenJ. HowardH. StauntonJ. MolterJ. ClarineJ. NevarezA. ChiangG.G. ApplemanJ.R. WebsterK.R. ReichS.H. Design of development candidate eFT226, a first in class inhibitor of eukaryotic initiation factor 4A RNA helicase.J. Med. Chem.202063115879595510.1021/acs.jmedchem.0c0018232470302
    [Google Scholar]
  20. ChenM. AsanumaM. TakahashiM. ShichinoY. MitoM. FujiwaraK. SaitoH. FloorS.N. IngoliaN.T. SodeokaM. DodoK. ItoT. IwasakiS. Dual targeting of DDX3 and eIF4A by the translation inhibitor rocaglamide A.Cell Chem. Biol.2021284475486.e810.1016/j.chembiol.2020.11.00833296667
    [Google Scholar]
  21. NugrohoB.W. EdradaR.A. WrayV. WitteL. BringmannG. GehlingM. ProkschP. An insecticidal rocaglamide derivatives and related compounds from Aglaia adorata (Meliaceae).Phytochemistry199951336737610.1016/S0031‑9422(98)00751‑1
    [Google Scholar]
  22. IshibashiF. SatasookC. IsmanM.B. TowersG.H.N. Instecticidal 1H-cyclopenta[b]benzofurans from Aglaia odorata.Phytochemistry199332230731010.1016/S0031‑9422(00)94986‑0
    [Google Scholar]
  23. NugrohoB.W. EdradaR.A. GussregenB. WrayV. WitteL. ProkschP. Insecticidal rocaglamide derivatives from Aglaia duppereana.Phytochemistry19974481455146110.1016/S0031‑9422(96)00763‑7
    [Google Scholar]
  24. GregeH. PacheT. BremB. BacherM. HoferO. Insecticidal flavaglines and other compounds from Fijian Aglaia species.Phytochemistry2001571576410.1016/S0031‑9422(00)00471‑411336261
    [Google Scholar]
  25. TrostB.M. GreenspanP.D. YangB.V. SaulnierM.G. An unusual oxidative cyclization. A synthesis and absolute stereochemical assignment of (-)-rocaglamide.J. Am. Chem. Soc.1990112249022902410.1021/ja00180a081
    [Google Scholar]
  26. ZhaoQ. Abou-HamdanH. DésaubryL. Recent advances in the synthesis of flavaglines, a family of potent bioactive natural compounds originating from traditional chinese medicine.Eur. J. Org. Chem.20162016365908591610.1002/ejoc.201600437
    [Google Scholar]
  27. DoblerM.R. BruceI. CederbaumF. CookeN.G. DiorazioL.J. HallR.G. IrvingE. Total synthesis of (+/-)-rocaglamide and some aryl analogues.Tetrahedron Lett.200142478281828410.1016/S0040‑4039(01)01807‑X
    [Google Scholar]
  28. DaveyA.E. TaylorR.J.K. A novel 1,3-dithiane-based cyclopenta-annellation procedure: Synthesis of the rocaglamide skeleton.Chem. Commun.19871252710.1039/c39870000025
    [Google Scholar]
  29. DaveyA.E. SchaefferM.J. TaylorR.J.K. Synthesis of the novel anti-leukaemic tetrahydrocyclopenta[b]benzofuran, rocaglamide and related synthetic studies.Chem. Commun.1991161137113910.1039/c39910001137
    [Google Scholar]
  30. GerardB. Jones IiG. PorcoJ.A. Jr A biomimetic approach to the rocaglamides employing photogeneration of oxidopyryliums derived from 3-hydroxyflavones.J. Am. Chem. Soc.200412642136201362110.1021/ja044798o15493911
    [Google Scholar]
  31. StoneS.D. LajkiewiczN.J. WhitesellL. HilmyA. PorcoJ.A. Jr Biomimetic kinetic resolution: Highly enantio- and diastereoselective transfer hydrogenation of aglain ketones to access flavagline natural products.J. Am. Chem. Soc.2015137152553010.1021/ja511728b25514979
    [Google Scholar]
  32. WangW. CencicR. WhitesellL. PelletierJ. PorcoJ.A.Jr Synthesis of aza-rocaglates via ESIPT-Mediated [3+2] photocycloaddition.Chemistry20162234120061201010.1002/chem.20160295327338157
    [Google Scholar]
  33. YuehH. GaoQ. PorcoJ.A.Jr BeelerA.B. A photochemical flow reactor for large scale syntheses of aglain and rocaglate natural product analogues.Bioorg. Med. Chem.201725236197620210.1016/j.bmc.2017.06.01028666859
    [Google Scholar]
  34. ThedeK. DiedrichsN. RagotJ.P. Stereoselective synthesis of (+/-)-rocaglaol analogues.Org. Lett.20046244595459710.1021/ol047990415548084
    [Google Scholar]
  35. AnS.E. JeongJ. BaskarB. LeeJ. SeoJ. RheeY.H. Gold(I)-catalyzed synthesis of highly substituted 2-cyclopentenones from 5-siloxypent-3-en-1-ynes.Chemistry20091544118371184110.1002/chem.20090182419806619
    [Google Scholar]
  36. BasmadjianC. ZhaoQ. DésaubryL. Exploratory studies toward a synthesis of flavaglines. A novel access to a highly substituted cyclopentenone intermediate.Tetrahedron Lett.201556572773010.1016/j.tetlet.2014.12.093
    [Google Scholar]
  37. Abou-HamdanH. DésaubryL. Unexpected inversion of configuration during the carbamoylation of 1-Azaflavaglines.Synlett202031202023202610.1055/s‑0040‑1707277
    [Google Scholar]
  38. ZhaoQ. Tijeras-RaballandA. de GramontA. RaymondE. DésaubryL. Bioisosteric modification of flavaglines.Tetrahedron Lett.201657262943294410.1016/j.tetlet.2016.05.089
    [Google Scholar]
  39. ChuJ. ZhangW. CencicR. O’ConnorP.B.F. RobertF. DevineW.G. SelznickA. HenkelT. MerrickW.C. BrownL.E. BaranovP.V. PorcoJ.A.Jr PelletierJ. Rocaglates induce gain-of-function alterations to eIF4A and eIF4F.Cell Rep.202030824812488.e510.1016/j.celrep.2020.02.00232101697
    [Google Scholar]
  40. Hernando-RodríguezB. Artal-SanzM. Mitochondrial quality control mechanisms and the PHB (Prohibitin) complex.Cells201871223810.3390/cells712023830501123
    [Google Scholar]
  41. AndeS.R. XuY.X.Z. MishraS. Prohibitin: A potential therapeutic target in tyrosine kinase signaling.Signal Transduct. Target. Ther.201721705910.1038/sigtrans.2017.5929263933
    [Google Scholar]
  42. Zi XuY.X. AndeS.R. MishraS. Prohibitin: A new player in immunometabolism and in linking obesity and inflammation with cancer.Cancer Lett.201841520821610.1016/j.canlet.2017.12.00129222040
    [Google Scholar]
  43. MishraS. NyombaB.G. Prohibitin - At the crossroads of obesity-linked diabetes and cancer.Exp. Biol. Med. (Maywood)2017242111170117710.1177/153537021770397628399645
    [Google Scholar]
  44. WangD. TabtiR. ElderwishS. DjehalA. ChouhaN. PinotF. YuP. NebigilC.G. DésaubryL. SFPH proteins as therapeutic targets for a myriad of diseases.Bioorg. Med. Chem. Lett.20203022, 127600.10.1016/j.bmcl.2020.12760033035678
    [Google Scholar]
  45. YurugiH. MariniF. WeberC. DavidK. ZhaoQ. BinderH. DésaubryL. RajalingamK. Targeting prohibitins with chemical ligands inhibits KRAS-mediated lung tumours.Oncogene201736334778478910.1038/onc.2017.9328414306
    [Google Scholar]
  46. YurugiH. ZhuangY. SiddiquiF.A. LiangH. RosigkeitS. ZengY. Abou-HamdanH. BockampE. ZhouY. AbankwaD. ZhaoW. DésaubryL. RajalingamK. A subset of flavaglines inhibits KRAS nanoclustering and activation.J. Cell Sci.202013312, jcs244111.10.1242/jcs.24411132501281
    [Google Scholar]
  47. YuanG. ChenX. LiuZ. WeiW. ShuQ. Abou-HamdanH. JiangL. LiX. ChenR. DésaubryL. ZhouF. XieD. Flavagline analog FL3 induces cell cycle arrest in urothelial carcinoma cell of the bladder by inhibiting the Akt/PHB interaction to activate the GADD45α pathway.J. Exp. Clin. Cancer Res.20183712110.1186/s13046‑018‑0695‑529415747
    [Google Scholar]
  48. JacksonD.N. AlulaK.M. Delgado-DeidaY. TabtiR. TurnerK. WangX. VenuprasadK. SouzaR.F. DésaubryL. TheissA.L. The synthetic small molecule FL3 combats intestinal tumorigenesis via axin1-mediated inhibition of Wnt/β-Catenin Signaling.Cancer Res.202080173519352910.1158/0008‑5472.CAN‑20‑021632665357
    [Google Scholar]
  49. PloegerC. HuthT. SugiyantoR.N. PuschS. GoeppertB. SingerS. TabtiR. HausserI. SchirmacherP. DésaubryL. RoesslerS. Prohibitin, STAT3 and SH2D4A physically and functionally interact in tumor cell mitochondria.Cell Death Dis.20201111102310.1038/s41419‑020‑03220‑333257655
    [Google Scholar]
  50. RibeiroN. ThuaudF. BernardY. GaiddonC. CresteilT. HildA. HirschE.C. MichelP.P. NebigilC.G. DésaubryL. Flavaglines as potent anticancer and cytoprotective agents.J. Med. Chem.20125522100641007310.1021/jm301201z23072299
    [Google Scholar]
  51. QureshiR. YildirimO. GasserA. BasmadjianC. ZhaoQ. WilmetJ.P. DésaubryL. NebigilC.G. FL3, a synthetic flavagline and ligand of prohibitins, protects cardiomyocytes via STAT3 from Doxorubicin toxicity.PLoS One20151011, e0141826.10.1371/journal.pone.014182626536361
    [Google Scholar]
  52. HanJ. ZhaoQ. BasmadjianC. DésaubryL. TheissA.L. Flavaglines ameliorate experimental colitis and protect against intestinal epithelial cell apoptosis and mitochondrial dysfunction.Inflamm. Bowel Dis.2016221556710.1097/MIB.000000000000059226398710
    [Google Scholar]
  53. Taroncher-OldenburgG. MüllerC. ObermannW. ZiebuhrJ. HartmannR.K. GrünwellerA. Targeting the DEAD-Box RNA helicase eIF4A with rocaglates-A pan-antiviral strategy for minimizing the impact of future RNA virus pandemics.Microorganisms20219354010.3390/microorganisms903054033807988
    [Google Scholar]
  54. MüllerC. ObermannW. KarlN. WendelH.G. Taroncher-OldenburgG. PleschkaS. HartmannR.K. GrünwellerA. ZiebuhrJ. The rocaglate CR-31-B (-) inhibits SARS-CoV-2 replication at non-cytotoxic, low nanomolar concentrations in vitro and ex vivo.Antiviral Res.2021186, 105012.10.1016/j.antiviral.2021.10501233422611
    [Google Scholar]
  55. MüllerC. ObermannW. SchulteF.W. Lange-GrünwellerK. OestereichL. ElgnerF. GlitscherM. HildtE. SinghK. WendelH-G. HartmannR.K. ZiebuhrJ. GrünwellerA. Comparison of broad-spectrum antiviral activities of the synthetic rocaglate CR-31-B (-) and the eIF4A-inhibitor Silvestrol.Antiviral Res.2020175, 104706.10.1016/j.antiviral.2020.10470631931103
    [Google Scholar]
  56. LiuS. WangW. BrownL.E. QiuC. LajkiewiczN. ZhaoT. ZhouJ. PorcoJ.A.Jr WangT.T. A novel class of small molecule compounds that inhibit hepatitis C virus infection by targeting the prohibitin-CRaf pathway.EBioMedicine20152111600160610.1016/j.ebiom.2015.09.01826870784
    [Google Scholar]
  57. ZhangW. LiuS. MaigaR.I. PelletierJ. BrownL.E. WangT.T. PorcoJ.A.Jr Chemical synthesis enables structural reengineering of aglaroxin c leading to inhibition bias for hepatitis C viral infection.J. Am. Chem. Soc.201914131312132310.1021/jacs.8b1147730590924
    [Google Scholar]
  58. ZhouX. XuL. WangY. WangW. SprengersD. MetselaarH.J. PeppelenboschM.P. PanQ. Requirement of the eukaryotic translation initiation factor 4F complex in hepatitis E virus replication.Antiviral Res.2015124111910.1016/j.antiviral.2015.10.01626526587
    [Google Scholar]
  59. FahrigT. GerlachI. HorváthE. A synthetic derivative of the natural product rocaglaol is a potent inhibitor of cytokine-mediated signaling and shows neuroprotective activity in vitro and in animal models of Parkinson’s disease and traumatic brain injury.Mol. Pharmacol.20056751544155510.1124/mol.104.00817715716464
    [Google Scholar]
  60. The Michael J. Fox Foundation for Parkinson’s ResearchIMD-026259: An innovative drug for diseasemodifying treatment of Parkinson’s disease.Available from: https://www.michaeljfox.org/grant/imd-026259-innovative-drug-disease-modifying-treatment-parkinsons-disease
  61. LiuT. NairS.J. LescarbeauA. BelaniJ. PelusoS. ConleyJ. TillotsonB. O’HearnP. SmithS. SlocumK. WestK. HelbleJ. DouglasM. BahadoorA. AliJ. McGovernK. FritzC. PalombellaV.J. WylieA. CastroA.C. TremblayM.R. Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors.J. Med. Chem.201255208859887810.1021/jm301154223025805
    [Google Scholar]
  62. MarionF. KalounE.B Lieby-MullerF. PerezM. AnnereauJ.P. CréancierL. Flavagline derivatives EP3164393A12018
    [Google Scholar]
  63. ThompsonP.A. EamB. YoungN.P. FishS. ChenJ. BarreraM. HowardH. SungE. ParraA. StauntonJ. ChiangG.G. Gerson-GurwitzA. WegerskiC.J. NevarezA. ClarineJ. SperryS. XiangA. NilewskiC. PackardG.K. MichelsT. TranC. SprengelerP.A. ErnstJ.T. ReichS.H. WebsterK.R. Targeting oncogene mRNA translation in B-Cell malignancies with eFT226, a potent and selective inhibitor of eIF4A.Mol. Cancer Ther.2021201263610.1158/1535‑7163.MCT‑19‑097333037136
    [Google Scholar]
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