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Tropoflavin

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(Redirected from7,8-Dihydroxyflavone)
Chemical compound
Pharmaceutical compound
Tropoflavin
Clinical data
Other names7,8-Dihydroxyflavone
Pharmacokinetic data
Bioavailability~5% (in mice)[1]
Eliminationhalf-life< 30 minutes (in mice)[1]
Identifiers
  • 7,8-Dihydroxy-2-phenyl-4H-chromen-4-one
CAS Number
PubChemCID
ChemSpider
UNII
ChEBI
CompTox Dashboard(EPA)
ECHA InfoCard100.048.903Edit this at Wikidata
Chemical and physical data
FormulaC15H10O4
Molar mass254.241 g·mol−1
3D model (JSmol)
  • c1ccc(cc1)c2cc(=O)c3ccc(c(c3o2)O)O
  • InChI=1S/C15H10O4/c16-11-7-6-10-12(17)8-13(19-15(10)14(11)18)9-4-2-1-3-5-9/h1-8,16,18H
  • Key:COCYGNDCWFKTMF-UHFFFAOYSA-N

Tropoflavin, also known as7,8-dihydroxyflavone (DHF), is anaturally occurringflavone found inGodmania aesculifolia,Tridax procumbens, andprimula tree leaves.[2][3][4] It has been found to act as apotent andselectivesmall-moleculeagonist of thetropomyosin receptor kinase B (TrkB) (Kd ≈ 320 nM), the mainsignaling receptor of theneurotrophinbrain-derived neurotrophic factor (BDNF).[5][6][7] Tropoflavin is bothorallybioavailable and able to penetrate theblood–brain barrier.[8][9] Aprodrug of tropoflavin with greatly improved potency andpharmacokinetics,R13 (and, formerly,R7), is under development for the treatment ofAlzheimer's disease.[10][11]

Tropoflavin has demonstrated therapeutic efficacy inanimal models of a variety ofcentral nervous system disorders,[7] includingdepression,[8]Alzheimer's disease,[12][13][14]cognitive deficits inschizophrenia,[15]Parkinson's disease,[5]Huntington's disease,[16]amyotrophic lateral sclerosis,[17]traumatic brain injury,[18]cerebral ischemia,[19][20]fragile X syndrome,[21] andRett syndrome.[22] Tropoflavin also shows efficacy in animal models of age-associatedcognitive impairment[23] and enhancesmemory consolidation andemotional learning in healthy rodents.[24][25] In addition, tropoflavin possesses powerfulantioxidant activity independent of its actions on the TrkB receptor,[26] and protects againstglutamate-inducedexcitotoxicity,[27]6-hydroxydopamine-induceddopaminergicneurotoxicity,[28] andoxidative stress-inducedgenotoxicity.[29] It was also found to blockmethamphetamine-induceddopaminergicneurotoxicity, an effect which, in contrast to the preceding,was found to be TrkB-dependent.[30]

In 2017, evidence was published suggesting that tropoflavin and various other reported small-molecule TrkB agonists might not actually be direct agonists of the TrkB and might be mediating their observed effects by other means.[31][32]

Tropoflavin has been found to act as a weakaromatase inhibitorin vitro (Ki = 10 μM),[33] though there is evidence to suggest that this might not be the casein vivo.[5] In addition, it has been found to inhibitaldehyde dehydrogenase andestrogen sulfotransferasein vitro (Ki = 35 μM and 1–3 μM, respectively), although similarly to the case of aromatase, these activities have not yet been confirmedin vivo.[5] Unlike many otherflavonoids, tropoflavin does not show any inhibitory activity on17β-hydroxysteroid dehydrogenase.[34] Tropoflavin has also been observed to possessin vitroantiestrogenic effects at very high concentrations (Ki = 50 μM).[35][36]

A variety of closestructural analogues of tropoflavin have also been found to act as TrkB agonistsin vitro, includingdiosmetin (5,7,3'-trihydroxy-4'-methoxyflavone),norwogonin (5,7,8-trihydroxyflavone),eutropoflavin (4'-dimethylamino-7,8-dihydroxyflavone),7,8,3'-trihydroxyflavone,7,3'-dihydroxyflavone,7,8,2'-trihydroxyflavone,3,7,8,2'-tetrahydroxyflavone, and3,7-dihydroxyflavone.[37] The highly hydroxylated analoguegossypetin (3,5,7,8,3',4'-hexahydroxyflavone), conversely, appears to be anantagonist of TrkBin vitro.[37]

Tropoflavin was also found to decrease mouse sleep in dark phase and reduce hypothalamus level oforexin A, but not orexin B, in mice.[38]

See also

[edit]

References

[edit]
  1. ^abUS application 20150274692, Keqiang Ye, "7,8-Dihydoxyflavone and 7,8-substituted flavone derivatives, compositions, and methods related thereto", published 2015-10-01, assigned to Emory University 
  2. ^Andero R, Ressler KJ (July 2012)."Fear extinction and BDNF: translating animal models of PTSD to the clinic".Genes, Brain and Behavior.11 (5):503–12.doi:10.1111/j.1601-183X.2012.00801.x.PMC 3389160.PMID 22530815.
  3. ^Colombo PS, Flamini G, Christodoulou MS, Rodondi G, Vitalini S, Passarella D, Fico G (February 2014). "Farinose alpine Primula species: phytochemical and morphological investigations".Phytochemistry.98:151–9.Bibcode:2014PChem..98..151C.doi:10.1016/j.phytochem.2013.11.018.hdl:2434/233766.PMID 24345641.
  4. ^Cell Press (2015)."Molecule found in tree leaves helps female mice combat weight gain; males unaffected". ScienceDaily. Retrieved2015-03-19.
  5. ^abcdJang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, Wilson WD, Xiao G, Blanchi B, Sun YE, Ye K (2010)."A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone".Proc. Natl. Acad. Sci. U.S.A.107 (6):2687–92.Bibcode:2010PNAS..107.2687J.doi:10.1073/pnas.0913572107.PMC 2823863.PMID 20133810.
  6. ^Liu X, Obianyo O, Chan CB, Huang J, Xue S, Yang JJ, Zeng F, Goodman M, Ye K (2014)."Biochemical and biophysical investigation of the brain-derived neurotrophic factor mimetic 7,8-dihydroxyflavone in the binding and activation of the TrkB receptor".J. Biol. Chem.289 (40):27571–84.doi:10.1074/jbc.M114.562561.PMC 4183797.PMID 25143381.
  7. ^abZeng Y, Wang X, Wang Q, Liu S, Hu X, McClintock SM (2013). "Small molecules activating TrkB receptor for treating a variety of CNS disorders".CNS Neurol Disord Drug Targets.12 (7):1066–77.doi:10.2174/18715273113129990089.PMID 23844685.
  8. ^abLiu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K, Phun LH, France S, Xiao G, Jia Y, Luo HR, Ye K (2010)."A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect".J. Med. Chem.53 (23):8274–86.doi:10.1021/jm101206p.PMC 3150605.PMID 21073191.
  9. ^Liu X, Chan CB, Qi Q, Xiao G, Luo HR, He X, Ye K (2012)."Optimization of a small tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression".J. Med. Chem.55 (19):8524–37.doi:10.1021/jm301099x.PMC 3491656.PMID 22984948.
  10. ^Chen C, Wang Z, Zhang Z, Liu X, Kang SS, Zhang Y, Ye K (January 2018)."The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer's disease".Proc. Natl. Acad. Sci. U.S.A.115 (3):578–583.Bibcode:2018PNAS..115..578C.doi:10.1073/pnas.1718683115.PMC 5777001.PMID 29295929.
  11. ^Liu C, Chan CB, Ye K (2016)."7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders".Translational Neurodegeneration.5 (1) 2.doi:10.1186/s40035-015-0048-7.PMC 4702337.PMID 26740873.
  12. ^Castello NA, Nguyen MH, Tran JD, Cheng D, Green KN, LaFerla FM (2014)."7,8-Dihydroxyflavone, a small molecule TrkB agonist, improves spatial memory and increases thin spine density in a mouse model of Alzheimer disease-like neuronal loss".PLOS ONE.9 (3) e91453.Bibcode:2014PLoSO...991453C.doi:10.1371/journal.pone.0091453.PMC 3948846.PMID 24614170.
  13. ^Chen C, Li XH, Zhang S, Tu Y, Wang YM, Sun HT (2014). "7,8-dihydroxyflavone ameliorates scopolamine-induced Alzheimer-like pathologic dysfunction".Rejuvenation Res.17 (3):249–54.doi:10.1089/rej.2013.1519.PMID 24325271.
  14. ^Zhang Z, Liu X, Schroeder JP, Chan CB, Song M, Yu SP, Weinshenker D, Ye K (2014)."7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer's disease".Neuropsychopharmacology.39 (3):638–50.doi:10.1038/npp.2013.243.PMC 3895241.PMID 24022672.
  15. ^Yang YJ, Li YK, Wang W, Wan JG, Yu B, Wang MZ, Hu B (2014). "Small-molecule TrkB agonist 7,8-dihydroxyflavone reverses cognitive and synaptic plasticity deficits in a rat model of schizophrenia".Pharmacol. Biochem. Behav.122:30–6.doi:10.1016/j.pbb.2014.03.013.PMID 24662915.S2CID 12198275.
  16. ^Jiang M, Peng Q, Liu X, Jin J, Hou Z, Zhang J, Mori S, Ross CA, Ye K, Duan W (2013)."Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington's disease".Hum. Mol. Genet.22 (12):2462–70.doi:10.1093/hmg/ddt098.PMC 3658168.PMID 23446639.
  17. ^Korkmaz OT, Aytan N, Carreras I, Choi JK, Kowall NW, Jenkins BG, Dedeoglu A (2014)."7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis".Neurosci. Lett.566:286–91.doi:10.1016/j.neulet.2014.02.058.PMC 5906793.PMID 24637017.
  18. ^Wu CH, Hung TH, Chen CC, Ke CH, Lee CY, Wang PY, Chen SF (2014)."Post-injury treatment with 7,8-dihydroxyflavone, a TrkB receptor agonist, protects against experimental traumatic brain injury via PI3K/Akt signaling".PLOS ONE.9 (11) e113397.Bibcode:2014PLoSO...9k3397W.doi:10.1371/journal.pone.0113397.PMC 4240709.PMID 25415296.
  19. ^Wang B, Wu N, Liang F, Zhang S, Ni W, Cao Y, Xia D, Xi H (2014). "7,8-dihydroxyflavone, a small-molecule tropomyosin-related kinase B (TrkB) agonist, attenuates cerebral ischemia and reperfusion injury in rats".J. Mol. Histol.45 (2):129–40.doi:10.1007/s10735-013-9539-y.PMID 24045895.S2CID 10671354.
  20. ^Uluc K, Kendigelen P, Fidan E, Zhang L, Chanana V, Kintner D, Akture E, Song C, Ye K, Sun D, Ferrazzano P, Cengiz P (2013)."TrkB receptor agonist 7, 8 dihydroxyflavone triggers profound gender- dependent neuroprotection in mice after perinatal hypoxia and ischemia".CNS Neurol Disord Drug Targets.12 (3):360–70.doi:10.2174/18715273113129990061.PMC 3674109.PMID 23469848.
  21. ^Tian M, Zeng Y, Hu Y, Yuan X, Liu S, Li J, Lu P, Sun Y, Gao L, Fu D, Li Y, Wang S, McClintock SM (2015). "7, 8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome".Neuropharmacology.89:43–53.doi:10.1016/j.neuropharm.2014.09.006.PMID 25229717.S2CID 38120522.
  22. ^Johnson RA, Lam M, Punzo AM, Li H, Lin BR, Ye K, Mitchell GS, Chang Q (2012)."7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome".J. Appl. Physiol.112 (5):704–10.doi:10.1152/japplphysiol.01361.2011.PMC 3643819.PMID 22194327.
  23. ^Zeng Y, Lv F, Li L, Yu H, Dong M, Fu Q (2012)."7,8-dihydroxyflavone rescues spatial memory and synaptic plasticity in cognitively impaired aged rats".J. Neurochem.122 (4):800–11.doi:10.1111/j.1471-4159.2012.07830.x.PMID 22694088.
  24. ^Bollen E, Vanmierlo T, Akkerman S, Wouters C, Steinbusch HM, Prickaerts J (2013). "7,8-Dihydroxyflavone improves memory consolidation processes in rats and mice".Behav. Brain Res.257:8–12.doi:10.1016/j.bbr.2013.09.029.PMID 24070857.S2CID 24088558.
  25. ^Andero R, Heldt SA, Ye K, Liu X, Armario A, Ressler KJ (2011)."Effect of 7,8-dihydroxyflavone, a small-molecule TrkB agonist, on emotional learning".Am J Psychiatry.168 (2):163–72.doi:10.1176/appi.ajp.2010.10030326.PMC 3770732.PMID 21123312.
  26. ^Foti M, Piattelli M, Baratta MT, Ruberto G (1996). "Flavonoids, Coumarins, and Cinnamic Acids as Antioxidants in a Micellar System. Structure−Activity Relationship†".Journal of Agricultural and Food Chemistry.44 (2):497–501.doi:10.1021/jf950378u.ISSN 0021-8561.
  27. ^Chen J, Chua KW, Chua CC, Yu H, Pei A, Chua BH, Hamdy RC, Xu X, Liu CF (2011). "Antioxidant activity of 7,8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicity".Neurosci. Lett.499 (3):181–5.doi:10.1016/j.neulet.2011.05.054.PMID 21651962.S2CID 36661121.
  28. ^Han X, Zhu S, Wang B, Chen L, Li R, Yao W, Qu Z (2014). "Antioxidant action of 7,8-dihydroxyflavone protects PC12 cells against 6-hydroxydopamine-induced cytotoxicity".Neurochem. Int.64:18–23.doi:10.1016/j.neuint.2013.10.018.PMID 24220540.S2CID 24439864.
  29. ^Zhang R, Kang KA, Piao MJ, Ko DO, Wang ZH, Chang WY, You HJ, Lee IK, Kim BJ, Kang SS, Hyun JW (2009)."Preventive effect of 7,8-dihydroxyflavone against oxidative stress induced genotoxicity".Biol. Pharm. Bull.32 (2):166–71.doi:10.1248/bpb.32.166.PMID 19182370.
  30. ^Ren Q, Zhang JC, Ma M, Fujita Y, Wu J, Hashimoto K (2014). "7,8-Dihydroxyflavone, a TrkB agonist, attenuates behavioral abnormalities and neurotoxicity in mice after administration of methamphetamine".Psychopharmacology.231 (1):159–66.doi:10.1007/s00213-013-3221-7.PMID 23934209.S2CID 17118439.
  31. ^Boltaev U, Meyer Y, Tolibzoda F, Jacques T, Gassaway M, Xu Q, Wagner F, Zhang YL, Palmer M, Holson E, Sames D (2017)."Multiplex quantitative assays indicate a need for reevaluating reported small-molecule TrkB agonists".Sci Signal.10 (493) eaal1670.doi:10.1126/scisignal.aal1670.PMID 28831019.
  32. ^Todd D, Gowers I, Dowler SJ, Wall MD, McAllister G, Fischer DF, Dijkstra S, Fratantoni SA, van de Bospoort R, Veenman-Koepke J, Flynn G, Arjomand J, Dominguez C, Munoz-Sanjuan I, Wityak J, Bard JA (2014)."A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease".PLOS ONE.9 (2) e87923.Bibcode:2014PLoSO...987923T.doi:10.1371/journal.pone.0087923.PMC 3913682.PMID 24503862.
  33. ^Kao YC, Zhou C, Sherman M, Laughton CA, Chen S (1998)."Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study".Environ. Health Perspect.106 (2):85–92.Bibcode:1998EnvHP.106...85K.doi:10.1289/ehp.9810685.PMC 1533021.PMID 9435150.
  34. ^Le Bail JC, Laroche T, Marre-Fournier F, Habrioux G (November 1998). "Aromatase and 17beta-hydroxysteroid dehydrogenase inhibition by flavonoids".Cancer Letters.133 (1):101–6.doi:10.1016/S0304-3835(98)00211-0.PMID 9929167.
  35. ^Le Bail JC, Varnat F, Nicolas JC, Habrioux G (1998). "Estrogenic and antiproliferative activities on MCF-7 human breast cancer cells by flavonoids".Cancer Lett.130 (1–2):209–16.doi:10.1016/S0304-3835(98)00141-4.PMID 9751276.
  36. ^Pouget C, Lauthier F, Simon A, Fagnere C, Basly JP, Delage C, Chulia AJ (2001). "Flavonoids: structural requirements for antiproliferative activity on breast cancer cells".Bioorg. Med. Chem. Lett.11 (24):3095–7.doi:10.1016/S0960-894X(01)00617-5.PMID 11720850.
  37. ^abLiu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K, et al. (December 2010)."A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect".Journal of Medicinal Chemistry.53 (23):8274–86.doi:10.1021/jm101206p.PMC 3150605.PMID 21073191.
  38. ^Feng P, Akladious AA, Hu Y, Raslan Y, Feng J, Smith PJ (October 2015). "7,8-Dihydroxyflavone reduces sleep during dark phase and suppresses orexin A but not orexin B in mice".Journal of Psychiatric Research.69:110–9.doi:10.1016/j.jpsychires.2015.08.002.PMID 26343602.
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