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Diosmetin

PubChem CID
5281612
Structure
Diosmetin_small.png
Diosmetin_3D_Structure.png
Molecular Formula
Synonyms
  • Diosmetin
  • 520-34-3
  • 5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-chromen-4-one
  • Luteolin 4'-methyl ether
  • 4'-Methylluteolin
Molecular Weight
300.26 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-06-24
  • Modify:
    2025-01-11
Description
Diosmetin is a monomethoxyflavone that is the 4'-methyl ether derivative of luteolin. It is a natural product isolated from citrus fruits which exhibits a range of pharmacological activities. It has a role as an antioxidant, an antineoplastic agent, a plant metabolite, a tropomyosin-related kinase B receptor agonist, an apoptosis inducer, an angiogenesis inhibitor, a cardioprotective agent, a bone density conservation agent, an anti-inflammatory agent and a vasodilator agent. It is a monomethoxyflavone, a trihydroxyflavone and a 3'-hydroxyflavonoid. It is functionally related to a luteolin. It is a conjugate acid of a diosmetin-7-olate.
Diosmetin is an O-methylated flavone and the aglycone part of the flavonoid glycosides diosmin that occurs naturally in citrus fruits. Pharmacologically, diosmetin is reported to exhibit anticancer, antimicrobial, antioxidant, oestrogenic and anti-inflamatory activities. It also acts as a weak TrkB receptor agonist.
Diosmetin has been reported in Lepisorus ussuriensis, Taraxacum sinicum, and other organisms with data available.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Diosmetin.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-one
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C16H12O6/c1-21-13-3-2-8(4-10(13)18)14-7-12(20)16-11(19)5-9(17)6-15(16)22-14/h2-7,17-19H,1H3
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

MBNGWHIJMBWFHU-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

COC1=C(C=C(C=C1)C2=CC(=O)C3=C(C=C(C=C3O2)O)O)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C16H12O6
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 HMDB ID

2.3.9 KEGG ID

2.3.10 Lipid Maps ID (LM_ID)

2.3.11 Metabolomics Workbench ID

2.3.12 Nikkaji Number

2.3.13 Pharos Ligand ID

2.3.14 Wikidata

2.3.15 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

diosmetin

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
300.26 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
1.7
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
6
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
300.06338810 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
300.06338810 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
96.2 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
22
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
462
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Color / Form

Yellow powder
LookChem; Look for Chemicals. Diosmetin (CAS 520-34-3). Available from, as of Dec 25, 2012: https://www.lookchem.com/cas-520/520-34-3.html

3.2.3 Melting Point

256-258 °C
LookChem; Look for Chemicals. Diosmetin (CAS 520-34-3). Available from, as of Dec 25, 2012: https://www.lookchem.com/cas-520/520-34-3.html
228 - 230 °C

3.2.4 Solubility

Chem Faces; Chem Faces Biological Chemical Co Ltd., Product Information Datasheet. Diosmetin (CAS 520-34-3), Oct 2012. Available from, as of Dec 25, 2012: https://www.chemfaces.com/manual/Diosmetin-CFN90210.pdf

3.2.5 Density

1.512 g/cu cm
LookChem; Look for Chemicals. Diosmetin (CAS 520-34-3). Available from, as of Dec 25, 2012: https://www.lookchem.com/cas-520/520-34-3.html

3.2.6 LogP

log Kow = 3.10
Perrissoud D, Testa B; Arzneim-Forsch 36: 1249-1253 (1986)
3.10

3.2.7 Stability / Shelf Life

Stable under recommended storage conditions.
Indofine Chemical Company, Inc; MSDS for Diosmetin, Edition 6.00, Revision Date 01/12/2011. Available from, as of February 19, 2013: https://www.indofinechemical.com/resources/msds/020082.pdf

3.2.8 Collision Cross Section

180.91 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

163.33 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111
164.8 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceuticals -> Metabolite of Diosmin
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043

3.3.2 Endocrine Disruptors

Potential endocrine disrupting compound
S109 | PARCEDC | List of 7074 potential endocrine disrupting compounds (EDCs) by PARC T4.2 | DOI:10.5281/zenodo.10944198

3.3.3 Lipids

Polyketides [PK] -> Flavonoids [PK12] -> Flavones and Flavonols [PK1211]

3.3.4 Polymers

Antioxidant (polyphenol)
S120 | DUSTCT2024 | Substances from Second NORMAN Collaborative Dust Trial | DOI:10.5281/zenodo.13835254

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 13C NMR Spectra

1 of 2
Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
Thumbnail
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2 of 2
Instrument Name
Bruker HX-90
Copyright
Copyright © 2002-2024 Wiley-VCH Verlag GmbH & Co. KGaA. All Rights Reserved.
Thumbnail
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4.2 Mass Spectrometry

4.2.1 GC-MS

1 of 2
Source of Spectrum
JC-474-374-0
Copyright
Copyright © 2020-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
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2 of 2
Source of Spectrum
Y4-78-273-0
Copyright
Copyright © 2020-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.2.2 MS-MS

1 of 6
View All
Spectra ID
Instrument Type
LC-ESI-QFT
Ionization Mode
positive
Top 5 Peaks

286.0471 79.30

301.071 20.45

183.0295 0.25

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Notes
adduct_type [M+H]+ original_collision_energy 35% nominal Data from FlavonoidSearch July 2020 LTQ-FT-ICR, Thermo Scientific
2 of 6
View All
Spectra ID
Instrument Type
LC-ESI-IT
Ionization Mode
positive
Top 5 Peaks

286.0453 91.90

301.0936 8.10

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Notes
adduct_type [M+H]+ original_collision_energy 35% nominal Data from FlavonoidSearch July 2020 LTQ Ion trap, Thermo Scientific

4.2.3 LC-MS

1 of 11
View All
Accession ID
Authors
Plant Biology, The Noble Foundation, Ardmore, OK, US/Dennis Fine, Daniel Wherritt, and Lloyd Sumner
Instrument
Bruker impact HD
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
NEGATIVE
Ionization
ESI
Collision Energy
20 eV
Column Name
Waters Acquity BEH C18 1.7um x 2.1 x 150 mm
Retention Time
634.2 sec
Precursor m/z
299.058
Precursor Adduct
[M-H]-
Top 5 Peaks

284.0347 999

299.058 300

285.0374 129

300.0611 34

Thumbnail
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License
CC BY-NC-SA
2 of 11
View All
Accession ID
Authors
Plant Biology, The Noble Foundation, Ardmore, OK, US/Dennis Fine, Daniel Wherritt, and Lloyd Sumner
Instrument
Bruker impact HD
Instrument Type
LC-ESI-QTOF
MS Level
MS
Ionization Mode
NEGATIVE
Ionization
ESI
Collision Energy
10 eV
Column Name
Waters Acquity BEH C18 1.7um x 2.1 x 150 mm
Retention Time
634.2 sec
Top 5 Peaks

299.056 999

300.0593 166

284.0321 165

285.0355 23

301.061 21

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License
CC BY-NC-SA

4.2.4 Other MS

1 of 3
View All
MS Category
Experimental
MS Type
Other
MS Level
MS2
Instrument Type
ESI-TOF
Ionization Mode
negative
Top 5 Peaks

227.0364 100

255.0317 49.25

284.0352 40.44

133.0296 37.84

107.0144 36.54

Thumbnail
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2 of 3
View All
MS Category
Experimental
MS Type
Other
MS Level
MS2
Instrument Type
ESI-TOF
Ionization Mode
negative
Top 5 Peaks

469.3332 100

939.675 85.09

940.6785 52.95

470.3365 26.43

941.6818 15.92

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4.3 IR Spectra

4.3.1 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Neat (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Indofine Chemical Company, Inc.
Catalog Number
20082
Lot Number
2080806
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.4 Raman Spectra

Technique
FT-Raman
Source of Spectrum
Forensic Spectral Research
Source of Sample
Indofine Chemical Company, Inc.
Catalog Number
20082
Lot Number
0208806
Copyright
Copyright © 2014-2024 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Labels

Drug and label
Active ingredient and drug

8 Food Additives and Ingredients

8.1 Associated Foods

9 Pharmacology and Biochemistry

9.1 Absorption, Distribution and Excretion

Absorption
Diosmin is hydrolyzed to its aglycone diosmetin by intestinal microflora enzymes before its absorption into the body.

9.2 Metabolism / Metabolites

... Diosmetin was metabolised to the structurally similar flavone luteolin in MDA-MB 468 cells, whereas no metabolism was seen in MCF-10A cells...
Androutsopoulos VP et al; Oncol Rep 21(6):1525-8 (2009)
Various types of tumors are known to overexpress enzymes belonging to the CYP1 family of cytochromes P450. The present study aimed to characterize the metabolism and further antiproliferative activity of the natural flavonoid diosmetin in the CYP1-expressing human hepatoma cell line HepG2. Diosmetin was converted to luteolin in HepG2 cells after 12 and 30 hr of incubation. In the presence of the CYP1A inhibitor alpha-naphthoflavone, the conversion of diosmetin to luteolin was attenuated. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays revealed luteolin to be more cytotoxic than diosmetin. The antiproliferative effect of diosmetin in HepG2 cells was attributed to blockage at the G2/M phase as determined by flow cytometry. Induction of G2/M arrest was accompanied by up-regulation of phospho-extracellular-signal-regulated kinase (p-ERK), phospho-c-jun N-terminal kinase, p53 and p21 proteins. More importantly, induction of G2/M arrest and p53 and p-ERK up-regulation were reversed by the application of the CYP1 inhibitor alpha-naphthoflavone. Taken together, the data provide new evidence on the tumor-suppressing role of cytochrome P450 CYP1A enzymes and extend the hypothesis that the anticancer activity of dietary flavonoids is enhanced by P450-activation.
Androutsopoulos VP and Spandidos DA ; J Nutr Biochem 24(2):496-504 (2013)
CYP1A1 and CYP1B1 are two extrahepatic enzymes that have been implicated in carcinogenesis and cancer progression. Selective inhibition of CYP1A1 and CYP1B1 by dietary constituents, notably the class of flavonoids, is a widely accepted paradigm that supports the concept of dietary chemoprevention. In parallel, recent studies have documented the ability of CYP1 enzymes to selectively metabolize dietary flavonoids to conversion products that inhibit cancer cell proliferation. In the present study /the authors/ have examined the inhibition of CYP1A1 and CYP1B1-catalyzed EROD activity by 14 different flavonoids containing methoxy- and hydroxyl-group substitutions as well as the metabolism of the monomethoxylated CYP1-flavonoid inhibitor acacetin and the poly-methoxylated flavone eupatorin-5-methyl ether by recombinant CYP1A1 and CYP1B1. The most potent inhibitors of CYP1-EROD activity were the methoxylated flavones acacetin, diosmetin, eupatorin and the di-hydroxylated flavone chrysin, indicating that the 4'-OCH(3) group at the B ring and the 5,7-dihydroxy motif at the A ring play a prominent role in EROD inhibition. Potent inhibition of CYP1B1 EROD activity was also obtained for the poly-hydroxylated flavonols quercetin and myricetin. HPLC metabolism of acacetin by CYP1A1 and CYP1B1 revealed the formation of the structurally similar flavone apigenin by demethylation at the 4'-position of the B ring, whereas the flavone eupatorin-5-methyl ether was metabolized to an as yet unidentified metabolite assigned E(5)M1. Eupatorin-5-methyl ether demonstrated a submicromolar IC50 in the CYP1-expressing cancer cell line MDA-MB 468, while it was considerably inactive in the normal cell line MCF-10A. Homology modeling in conjunction with molecular docking calculations were employed in an effort to rationalize the activity of these flavonoids based on their CYP1-binding mode. Taken together the data suggest that dietary flavonoids exhibit three distinct modes of action with regard to cancer prevention, based on their hydroxyl and methoxy decoration: (1) inhibitors of CYP1 enzymatic activity, (2) CYP1 substrates and (3) substrates and inhibitors of CYP1 enzymes.
Androutsopoulos VP et al; Bioorg Med Chem 19(9):2842-9 (2011)
Flos Chrysanthemi (the flower of Chrysanthemum morifolium Ramat.) is widely used in China as a food and traditional Chinese medicine for many diseases. Luteolin and apigenin are two main bioactive components in Flos Chrysanthemi, and chrysoeriol and diosmetin are two methylated metabolites of luteolin in vivo by cathechol-O-methyltransferase (COMT). However, there was /a/ lack of pharmacokinetic information of chrysoeriol and diosmetin after oral administration of Flos Chrysanthemi extract (FCE). The present study aimed to develop an HPLC-UV method for simultaneous determination of rat plasma concentration of luteolin, apigenin, chrysoeriol and diosmetin and utilize it in pharmacokinetic study of the four compounds after orally giving FCE to rats. The method was successfully validated and applied to the pharmacokinetic study when oral administration of FCE to rats with or without co-giving a COMT inhibitor, entacapone. Chrysoeriol and diosmetin were detected in rat plasma after oral administration of FCE and their concentrations were significantly decreased after co-giving entacapone... In conclusion, a sensitive, accurate and reproducible HPLC-UV method for simultaneous determination of luteolin, apigenin, chrysoeriol and diosmetin in rat plasma were developed, pharmacokinetics of chrysoeriol and diosmetin combined with luteolin and apigenin were characterized after oral administration of FCE to rats, which gave us more information on pharmacokinetics and potential pharmacological effects of FCE in vivo.
Chen Z et al; Fitoterapia 83(8):1616-22 (2012)
Diosmetin has known human metabolites that include (2S,3S,4S,5R)-3,4,5-Trihydroxy-6-[5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-oxochromen-7-yl]oxyoxane-2-carboxylic acid.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

9.3 Mechanism of Action

Various types of tumors are known to overexpress enzymes belonging to the CYP1 family of cytochromes P450. The present study aimed to characterize the metabolism and further antiproliferative activity of the natural flavonoid diosmetin in the CYP1-expressing human hepatoma cell line HepG2. Diosmetin was converted to luteolin in HepG2 cells after 12 and 30 hr of incubation. In the presence of the CYP1A inhibitor alpha-naphthoflavone, the conversion of diosmetin to luteolin was attenuated. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays revealed luteolin to be more cytotoxic than diosmetin. The antiproliferative effect of diosmetin in HepG2 cells was attributed to blockage at the G2/M phase as determined by flow cytometry. Induction of G2/M arrest was accompanied by up-regulation of phospho-extracellular-signal-regulated kinase (p-ERK), phospho-c-jun N-terminal kinase, p53 and p21 proteins. More importantly, induction of G2/M arrest and p53 and p-ERK up-regulation were reversed by the application of the CYP1 inhibitor alpha-naphthoflavone. Taken together, the data provide new evidence on the tumor-suppressing role of cytochrome P450 CYP1A enzymes and extend the hypothesis that the anticancer activity of dietary flavonoids is enhanced by P450-activation.
Androutsopoulos VP and Spandidos DA ; J Nutr Biochem 24(2):496-504 (2013)
CYP1A1 and CYP1B1 are two extrahepatic enzymes that have been implicated in carcinogenesis and cancer progression. Selective inhibition of CYP1A1 and CYP1B1 by dietary constituents, notably the class of flavonoids, is a widely accepted paradigm that supports the concept of dietary chemoprevention. In parallel, recent studies have documented the ability of CYP1 enzymes to selectively metabolize dietary flavonoids to conversion products that inhibit cancer cell proliferation. In the present study /the authors/ have examined the inhibition of CYP1A1 and CYP1B1-catalyzed EROD activity by 14 different flavonoids containing methoxy- and hydroxyl-group substitutions as well as the metabolism of the monomethoxylated CYP1-flavonoid inhibitor acacetin and the poly-methoxylated flavone eupatorin-5-methyl ether by recombinant CYP1A1 and CYP1B1. The most potent inhibitors of CYP1-EROD activity were the methoxylated flavones acacetin, diosmetin, eupatorin and the di-hydroxylated flavone chrysin, indicating that the 4'-OCH(3) group at the B ring and the 5,7-dihydroxy motif at the A ring play a prominent role in EROD inhibition. Potent inhibition of CYP1B1 EROD activity was also obtained for the poly-hydroxylated flavonols quercetin and myricetin. HPLC metabolism of acacetin by CYP1A1 and CYP1B1 revealed the formation of the structurally similar flavone apigenin by demethylation at the 4'-position of the B ring, whereas the flavone eupatorin-5-methyl ether was metabolized to an as yet unidentified metabolite assigned E(5)M1. Eupatorin-5-methyl ether demonstrated a submicromolar IC50 in the CYP1-expressing cancer cell line MDA-MB 468, while it was considerably inactive in the normal cell line MCF-10A. Homology modeling in conjunction with molecular docking calculations were employed in an effort to rationalize the activity of these flavonoids based on their CYP1-binding mode. Taken together the data suggest that dietary flavonoids exhibit three distinct modes of action with regard to cancer prevention, based on their hydroxyl and methoxy decoration: (1) inhibitors of CYP1 enzymatic activity, (2) CYP1 substrates and (3) substrates and inhibitors of CYP1 enzymes.
Androutsopoulos VP et al; Bioorg Med Chem 19(9):2842-9 (2011)
The binding mechanism of molecular interaction between diosmetin and human serum albumin (HSA) in a pH 7.4 phosphate buffer was studied using atomic force microscopy (AFM) and various spectroscopic techniques including fluorescence, resonance light scattering (RLS), UV-vis absorption, circular dichroism (CD), and Fourier transform infrared (FT-IR) spectroscopy. Fluorescence data revealed that the fluorescence quenching of HSA by diosmetin was a static quenching procedure. The binding constants and number of binding sites were evaluated at different temperatures. The RLS spectra and AFM images showed that the dimension of the individual HSA molecules were larger after interaction with diosmetin. The thermodynamic parameters, /changes in enthalpy and entropy/ were calculated to be -24.56 kJ/mol and 14.67 J/mol/K, respectively, suggesting that the binding of diosmtin to HSA was driven mainly by hydrophobic interactions and hydrogen bonds. The displacement studies and denaturation experiments in the presence of urea indicated site I as the main binding site for diosmetin on HSA. The binding distance between diosmetin and HSA was determined to be 3.54 nm based on the Forster theory. Analysis of CD and FT-IR spectra demonstrated that HSA conformation was slightly altered in the presence of diosmetin.
Zhang G et al; J Agric Food Chem 60(10):2721-9 (2012)
The survival of osteoblasts is one of the determinants of the development of osteoporosis. This study /investigates/ the osteoblastic differentiation induced by diosmetin, a flavonoid derivative, in osteoblastic cell lines MG-63, hFOB, and MC3T3-E1 and bone marrow stroma cell line M2-10B4. Osteoblastic differentiation was determined by assaying alkaline phosphatase (ALP) activity and mineralization degree and measuring various osteoblast-related markers using ELISA. Expression and phosphorylation of Runt-related transcription factor 2 (Runx2), protein kinase Cdelta (PKCdelta), extracellular signal-regulated kinase (ERK), p38, and c-jun-N-terminal kinase (JNK) was assessed by immunoblot. Rac1 activity was determined by immunoprecipitation, and Runx2 activity was assessed by EMSA. Genetic inhibition was performed by small hairpin RNA plasmids or small interfering RNA (siRNA) transfection. Diosmetin exhibited an effect on osteoblastic maturation and differentiation by means of ALP activity, osteocalcin, osteopontin, and type I collagen production, as well as Runx2 upregulation. Induction of differentiation by diosmetin was associated with increased PKCdelta phosphorylation and the activations of Rac1 and p38 and ERK1/2 kinases. Blocking PKCdelta by siRNA inhibition significantly decreased osteoblastic differentiation by inhibiting Rac1 activation and subsequently attenuating the phosphorylation of p38 and ERK1/2. In addition, blocking p38 and ERK1/2 by siRNA transfection also suppressed diosmetin-induced cell differentiation. /This shows/ that diosmetin induced osteoblastic differentiation through the PKCdelta-Rac1-MEK3/6-p38 and PKCdelta-Rac1-MEK1/2- ERK1/2-Runx2 pathways and that it is a promising agent for treating osteoporosis.
Hsu YL and Kuo PL; J Bone Miner Res 23 (6): 949-60 (2008)

9.4 Human Metabolite Information

9.4.1 Cellular Locations

Membrane

9.5 Transformations

10 Use and Manufacturing

10.1 Uses

EPA CPDat Chemical and Product Categories
The Chemical and Products Database, a resource for exposure-relevant data on chemicals in consumer products, Scientific Data, volume 5, Article number: 180125 (2018), DOI:10.1038/sdata.2018.125
Has use in reference standards, pharmacological research, food research, cosmetic research, synthetic precursor compounds, intermediates and fine chemicals, and as an ingredient in food supplements and beverages
Chem Faces; Chem Faces Biological Chemical Co Ltd., Product Information Datasheet. Diosmetin (CAS 520-34-3), Oct 2012. Available from, as of Dec 25, 2012: https://www.chemfaces.com/manual/Diosmetin-CFN90210.pdf
Pharmacology use as a natural flavonoid that can inhibit the activity of human CYP1A enzyme have antimutagenic and anti-allergic characters
Aurora; Aurora Chemical Company. Diosmetin (data sheet 2005). Available form, as of Dec 25, 2012: https://www.aurorachem.com/Diosmetin_1104.html
Aldose-Reductase-Inhibitor; Antimutagenic; Antirhinoviral; Antiviral; Cancer-Preventative
USDA; Dr. Duke's Phytochemical and Ethnobotanical Databases. Plants with a chosen chemical. Diosmetin. Washington, DC: US Dept Agric, Agric Res Service. Available from, as of Dec 25, 2012: https://www.ars-grin.gov/duke/

10.2 Methods of Manufacturing

Prepared from diosmin isolated from various plants sources.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 558

10.3 General Manufacturing Information

Diosmetin is available in food supplements containing citrus bioflavonoids
RD; Right Diagnosis. Available from, as of Dec 25, 2012: https://www.rightdiagnosis.com/vitamin/diosmetin.htm

11 Identification

11.1 Analytic Laboratory Methods

...Polyamide column chromatography and UV spectrometry were used in the analysis of the constituents of the flowers, leaves and rhizomes of some species of Centranthus. Results showed that rutin, robinin, quercetin (I) and kaempferol (II) were identified in the leaves of Centranthus ruber DC var. albiflorus Zola. Luteolin, I and II were found in C. angustifolius (Miller) DC. leaves, and diosmetin, I and II in C. calcitrapa (L.) Dufresne leaves. Valepotriates were present in the methylene chloride extracts of the rhizomes, leaves and flowers of all species.
Pagani F et al; Boll. Chim. Farm 120:463-468, (1981)
Simultaneous determination of diosmin and diosmetin in human plasma by ion trap liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry: Application to a clinical pharmacokinetic study...
Werner E et al; J Pharm Biomed Anal 53(4):1070-1 (2010)
The isolation and identification of 3 new flavanol 7-glucuronides, luteolin 7-glucuronide (luteolin 7-O-glucuronide), apigenin 7-glucuronide and diosmetin 7-glucuronide, from the seeds of Alyssum minimum are described.
Afsharypuor S and GB Lockwood: J. Nat. Prod.; 49:944-945 (1986)
From the leaves and twigs of Leptadenia reticulata, hentriacontanol, alpha-amyrin, beta-amyrin, and stigmasterol were isolated and identified. Two flavones, diosmetin and luteolin, were also isolated and characterized by chemical and spectral methods.
Krishna PVG et al; Planta Med 27:395-400, (1975)

11.2 Clinical Laboratory Methods

Diosmetin and hesperetin are the aglycones of the flavonoid glycosides diosmin and hesperidin which occur naturally in citrus fruit. A GC/MS method for the simultaneous determination of diosmetin and hesperetin in human plasma and urine has been developed and validated. The method was linear in the 2-300 ng/mL concentration range for both diosmetin and hesperetin in plasma and urine (r > 0.999). The precision of the method was better than 6.01 and 7.16% for diosmetin and hesperetin, respectively, and the accuracy was 96.76-100.40% and 95.00-105.50% for diosmetin and hesperetin, respectively. The lower limit of quantitation was found to be 2 ng/mL for both analytes in plasma and urine. Recovery of diosmetin, hesperetin and internal standard naringenin was greater than 82.5%. The method has been applied for the determination of diosmetin and hesperetin in plasma and urine samples obtained from a healthy male subject following a single oral 1000 mg dose of the flavonoid glycoside diosmin. The presence of hesperetin in plasma and urine samples indicates the metabolic reduction of diosmetin to its flavanone analogue hesperetin through reduction of the 2,3 double bond of the C-ring by the enzymes of bacteria of the intestinal microflora.
Spanakis M et al; Biomed Chromatogr 23(2):124-31 (2009)
Diosmetin (3',5,7-trihydroxy-4'-methoxyflavone) is the aglycone of the flavonoid glycoside diosmin (3',5,7-trihydroxy-4'-methoxyflavone-7-ramnoglucoside). Diosmin is hydrolyzed by enzymes of intestinal micro flora before absorption of its aglycone diosmetin. A specific, sensitive, precise, accurate and robust HPLC assay for the simultaneous determination of diosmin and diosmetin in human plasma was developed and validated. Plasma samples were incubated with beta-glucuronidase/sulphatase. The analytes were isolated by liquid-liquid extraction with tert-butyl methyl ether at pH 2, and separated on a C(18) reversed-phase column using a mixture of methanol/1% formic acid (58:42, v/v) at a flow rate of 0.5 mL/min. APCI in the positive ion mode and multiple reaction monitoring (MRM) method was employed. The selected transitions for diosmin, diosmetin and the internal standard (7-ethoxycoumarin) at /mass to charge ration/ (m/z) were: 609.0 /to/ 463.0, 301.2 /to/ 286.1 and 191, respectively. A good linearity was found in the range of 0.25-500 ng/ml (R(2)>0.992) for both compounds. The intra-batch assay precision (CV) for diosmin and diosmetin ranged from 1.5% to 11.2% and from 2.8% to 12.5%, respectively, and the inter-batch precision were from 5.2% to 11.5% and 8.5% to 9.8%, respectively. The accuracy was well within the acceptable range the accuracies (from -2.7% to 4.2% and -1.6% to 3.5% for diosmin and diosmetin, respectively). The mean recoveries of diosmin, diosmetin and the internal standard were 87.5%, 89.2% and 67.2%. Stability studies showed that diosmin and diosmetin were stable in different conditions. Finally, the method was successfully applied to the pharmacokinetic study of diosmin in healthy volunteers following a single oral administration (Daflon).
Campanero MA et al; J Pharm Biomed Anal. 51(4):875-81 (2010)
HPLC determination in biological fluids.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 558

12 Safety and Hazards

12.1 Hazards Identification

12.1.1 GHS Classification

Note
Pictograms displayed are for 95.2% (40 of 42) of reports that indicate hazard statements. This chemical does not meet GHS hazard criteria for 4.8% (2 of 42) of reports.
Pictogram(s)
Irritant
Signal
Warning
GHS Hazard Statements
H302 (95.2%): Harmful if swallowed [Warning Acute toxicity, oral]
Precautionary Statement Codes

P264, P270, P301+P317, P330, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 42 reports by companies from 2 notifications to the ECHA C&L Inventory.

Reported as not meeting GHS hazard criteria per 2 of 42 reports by companies. For more detailed information, please visit ECHA C&L website.

There is 1 notification provided by 40 of 42 reports by companies with hazard statement code(s).

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

12.1.2 Hazard Classes and Categories

Acute Tox. 4 (95.2%)

12.2 Fire Fighting

12.2.1 Fire Fighting Procedures

Extinguishing media: Carbon dioxide, dry powder.
Indofine Chemical Company, Inc; MSDS for Diosmetin, Edition 6.00, Revision Date 01/12/2011. Available from, as of February 19, 2013: https://www.indofinechemical.com/resources/msds/020082.pdf
Wear an autonomous breathing apparatus and suitable protection clothing against chemical agents.
Indofine Chemical Company, Inc; MSDS for Diosmetin, Edition 6.00, Revision Date 01/12/2011. Available from, as of February 19, 2013: https://www.indofinechemical.com/resources/msds/020082.pdf

12.3 Accidental Release Measures

12.3.1 Cleanup Methods

Clean-up without creating dust and place in adapted and sealed containers for elimination. Wash the contaminated area with water and soap. Confine washing water and dispose of it complying with the local regulations. After cleaning, quickly eliminate traces of water with a product absorbing liquids (for example: sand, sawdust, universal binder, Kieselguhr).
Indofine Chemical Company, Inc; MSDS for Diosmetin, Edition 6.00, Revision Date 01/12/2011. Available from, as of February 19, 2013: https://www.indofinechemical.com/resources/msds/020082.pdf

12.3.2 Disposal Methods

SRP: Criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

12.3.3 Preventive Measures

Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.
Sigma-Aldrich; Material Safety Data Sheet for Diosmetin, Product Number: D7321, Version 5.0 (Revision Date 03/26/2013). Available from, as of June 5, 2013: https://www.sigmaaldrich.com/catalog/search?interface=All&term=520-34-3&lang=en&region=US&focus=product&N=0+220003048+219853269+219853286
Avoid formation of dust. Avoid contact with skin and eyes. During handling, wear suitable personal protective equipment.
Indofine Chemical Company, Inc; MSDS for Diosmetin, Edition 6.00, Revision Date 01/12/2011. Available from, as of February 19, 2013: https://www.indofinechemical.com/resources/msds/020082.pdf

12.4 Handling and Storage

12.4.1 Storage Conditions

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: 2-8 °C
Sigma-Aldrich; Material Safety Data Sheet for Diosmetin, Product Number: D7321, Version 5.0 (Revision Date 03/26/2013). Available from, as of June 5, 2013: https://www.sigmaaldrich.com/catalog/search?interface=All&term=520-34-3&lang=en&region=US&focus=product&N=0+220003048+219853269+219853286
Keep container tightly closed in a dry and well-ventilated place, away from light.
Indofine Chemical Company, Inc; MSDS for Diosmetin, Edition 6.00, Revision Date 01/12/2011. Available from, as of February 19, 2013: https://www.indofinechemical.com/resources/msds/020082.pdf

12.5 Exposure Control and Personal Protection

12.5.1 Personal Protective Equipment (PPE)

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). Hand protection: Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. Eye protection: Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). Skin and body protection: Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.
Sigma-Aldrich; Material Safety Data Sheet for Diosmetin, Product Number: D7321, Version 5.0 (Revision Date 03/26/2013). Available from, as of June 5, 2013: https://www.sigmaaldrich.com/catalog/search?interface=All&term=520-34-3&lang=en&region=US&focus=product&N=0+220003048+219853269+219853286
Wear imperatively an appropriated mask/respirator, tested and approved by standards such as NIOSH (US) or CEN (EU). ... Handle with protective gloves. The selected gloves have to satisfy the specifications of EU Directive 89/686/EEC and the standard EN 374 derived from it. ... Wear safety glasses. ... Wear suitable protective clothing according to the quantity and the level of activity of the substance at the workplace.
Indofine Chemical Company, Inc; MSDS for Diosmetin, Edition 6.00, Revision Date 01/12/2011. Available from, as of February 19, 2013: https://www.indofinechemical.com/resources/msds/020082.pdf

12.6 Regulatory Information

REACH Registered Substance

12.7 Other Safety Information

12.7.1 Toxic Combustion Products

Harmful/toxic vapors, carbon oxides may be released during the fire.
Indofine Chemical Company, Inc; MSDS for Diosmetin, Edition 6.00, Revision Date 01/12/2011. Available from, as of February 19, 2013: https://www.indofinechemical.com/resources/msds/020082.pdf

13 Toxicity

13.1 Toxicological Information

13.1.1 Antidote and Emergency Treatment

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1

13.1.2 Human Toxicity Excerpts

/ALTERNATIVE and IN VITRO TESTS/ The aim of this study was to assess the effects of diosmetin and hesperetin, two flavonoids present in various medicinal products, on CYP2C8 activity of human liver microsomes using paclitaxel oxidation to 6alpha-hydroxy-paclitaxel as a probe reaction. Diosmetin and hesperetin inhibited 6alpha-hydroxy-paclitaxel production in a concentration-dependent manner, diosmetin being about 16-fold more potent than hesperetin (mean IC50) values 4.25 +/- 0.02 and 68.5 +/- 3.3 uM for diosmetin and hesperetin, respectively). Due to the low inhibitory potency of hesperetin, we characterized the mechanism of diosmetin-induced inhibition only. This flavonoid proved to be a reversible, dead-end, full inhibitor of CYP2C8, its mean inhibition constant (Ki) being 3.13 +/- 0.11 uM. Kinetic analysis showed that diosmetin caused mixed-type inhibition, since it significantly decreased the Vmax (maximum velocity) and increased the Km value (substrate concentration yielding 50% of Vmax) of the reaction. The results of kinetic analyses were consistent with those of molecular docking simulation, which showed that the putative binding site of diosmetin coincided with the CYP2C8 substrate binding site. The demonstration that diosmetin inhibits CYP2C8 at concentrations similar to those observed after in vivo administration (in the low micromolar range) is of potential clinical relevance, since it may cause pharmacokinetic interactions with co-administered drugs metabolized by this CYP.
Quintieri L et al; Drug Metab Pharmacokinet 26 (6): 559-68 (2011)
/ALTERNATIVE and IN VITRO TESTS/ The survival of osteoblasts is one of the determinants of the development of osteoporosis. This study /investigates/ the osteoblastic differentiation induced by diosmetin, a flavonoid derivative, in osteoblastic cell lines MG-63, hFOB, and MC3T3-E1 and bone marrow stroma cell line M2-10B4. Osteoblastic differentiation was determined by assaying alkaline phosphatase (ALP) activity and mineralization degree and measuring various osteoblast-related markers using ELISA. Expression and phosphorylation of Runt-related transcription factor 2 (Runx2), protein kinase Cdelta (PKCdelta), extracellular signal-regulated kinase (ERK), p38, and c-jun-N-terminal kinase (JNK) was assessed by immunoblot. Rac1 activity was determined by immunoprecipitation, and Runx2 activity was assessed by EMSA. Genetic inhibition was performed by small hairpin RNA plasmids or small interfering RNA (siRNA) transfection. Diosmetin exhibited an effect on osteoblastic maturation and differentiation by means of ALP activity, osteocalcin, osteopontin, and type I collagen production, as well as Runx2 upregulation. Induction of differentiation by diosmetin was associated with increased PKCdelta phosphorylation and the activations of Rac1 and p38 and ERK1/2 kinases. Blocking PKCdelta by siRNA inhibition significantly decreased osteoblastic differentiation by inhibiting Rac1 activation and subsequently attenuating the phosphorylation of p38 and ERK1/2. In addition, blocking p38 and ERK1/2 by siRNA transfection also suppressed diosmetin-induced cell differentiation. /This shows/ that diosmetin induced osteoblastic differentiation through the PKCdelta-Rac1-MEK3/6-p38 and PKCdelta-Rac1-MEK1/2- ERK1/2-Runx2 pathways and that it is a promising agent for treating osteoporosis.
Hsu YL and Kuo PL; J Bone Miner Res 23(6):949-60 (2008)
/ALTERNATIVE and IN VITRO TESTS/ Flavonoids constitute a large class of polyphenolic compounds with cancer preventative properties. /This study/ examined the ability of the natural flavone diosmetin to inhibit proliferation of breast adenocarcinoma MDA-MB 468 and normal breast MCF-10A cells and found that this compound is selective for the cancer cells with slight toxicity in the normal breast cells... Diosmetin caused G1 arrest at 10 uM in MDA-MB 468 cells after 48 hr treatment whereas this effect was not observed in MCF-10A cells. /Data/ suggest that diosmetin exerts cytostatic effects in MDA-MB 468 cells, due to CYP1A1 and CYP1B1 catalyzed conversion to the flavone luteolin.
Androutsopoulos VP et al; Oncol Rep 21(6):1525-8 (2009)
/ALTERNATIVE and IN VITRO TESTS/ The aim of this study was to assess the effects of diosmetin and hesperetin, two flavonoids present in various medicinal products, on CYP2C8 activity of human liver microsomes using paclitaxel oxidation to 6alpha-hydroxy-paclitaxel as a probe reaction. Diosmetin and hesperetin inhibited 6alpha-hydroxy-paclitaxel production in a concentration-dependent manner, diosmetin being about 16-fold more potent than hesperetin (mean IC50) values 4.25 +/- 0.02 and 68.5 +/- 3.3 uM for diosmetin and hesperetin, respectively). Due to the low inhibitory potency of hesperetin, /investigators/ characterized the mechanism of diosmetin-induced inhibition only. This flavonoid proved to be a reversible, dead-end, full inhibitor of CYP2C8, its mean inhibition constant (Ki) being 3.13 +/- 0.11 uM. Kinetic analysis showed that diosmetin caused mixed-type inhibition, since it significantly decreased the maximum velocity/(Vmax)/and increased /the/ substrate concentration yielding 50% of Vmax (Km) of the reaction. The results of kinetic analyses were consistent with those of molecular docking simulation, which showed that the putative binding site of diosmetin coincided with the CYP2C8 substrate binding site. The demonstration that diosmetin inhibits CYP2C8 at concentrations similar to those observed after in vivo administration (in the low micromolar range) is of potential clinical relevance, since it may cause pharmacokinetic interactions with co-administered drugs metabolized by this CYP.
Quintieri L et al; Drug Metab Pharmacokinet 26 (6): 559-68 (2011)
For more Human Toxicity Excerpts (Complete) data for Diosmetin (7 total), please visit the HSDB record page.

13.1.3 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The new natural flavonoid compounds - diosmetin 7-O-beta-L-arabinofuranosyl (1 /to/ 2) beta-D-apiofuranoside (1) and diosmetin 7-O-beta-D-apiofuranoside (2) - were isolated from the acetone extract of date fruits epicarp belonging to family Arecaceae (Palmae). Elucidation of their chemical structures was determined by different spectroscopic methods in addition to the chemical and physical methods of analysis. These compounds were assessed for their biological activity on alloxan diabetic rats. A dose of 1.5 mL of (1) and (2) suspensions/100 gm b. wt were orally administrated to alloxan diabetic rats for 30 days. The treatment of diabetic rats with these compounds resulted in marked improvement of the different biochemical results, i.e. the serum glucose level (highly significant, from 330 + 5.5 mg/dL to 140 + 1.2 mg/dL) treated with (1); liver functions markedly developed both by AST and ALT levels, (reduced significantly from 68.3 + 4.8 u/L to 54 + 5.5 u/L and from 61.0 + 3.6 u/L to 40.1 + 3.6 u/L, respectively) treated with (2), accompanying with mild decrease in both cholesterol and triglycerides levels with (1) or (2). Decrease of TBARS level was observed in whole blood when treated with (1) or (2), while levels of glutathione peroxidase and superoxide dismutase were increased in liver. Serum testosterone level was highly significantly increased (from 705.1 + 3.6 mg/100 mL to 720 + 4.7 mg/100 mL), total acid phosphatase and prostate acid phosphatase activities were highly significantly decreased (from 16.9 + 0.28 u/L to 10.7 + 1.2 u/L and from 9.7 + 0.7 u/L to 6.5 + 1 u/L, respectively) for compound (1).
Michael HN et al; Phytother Res 27 (5): 699-704 (2013)
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Diosmetin (DGVL) extracted from the traditional Chinese herb Galium verum L. has been found to have anticancer activity. In this study, the effects of DGVL on the thymus of U14-bearing mice were investigated. Using flow cytometry, peripheral blood lymphocytes were characterized based on the expression of surface markers for T helper cells (CD4+) and T suppressor cells (CD8+). Serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin-2 (IL-2), IL-10, and transforming growth factor beta1 (TGF-beta1) and a cell proliferation assay were determined with an enzyme-linked immunosorbent assay. The expression of Fas and Fas ligand (FasL) on the thymus was determined by Western blotting. /The/ results showed that DGVL inhibited tumor growth and significantly increased the thymus weight compared with the control. Also, DGVL elevated serum levels of IL-2 and significantly reduced levels of TNF-alpha, TGF-beta1, and IL-10 in a dose-dependent manner. Histological study and terminal dUTP nick end labeling staining results showed that DGVL protected thymus tissue against the onslaught of tumor growth by inhibiting thymus lymphocyte apoptosis. The cell proliferation assay revealed that DGVL might promote more thymus lymphocytes towards proliferation. Furthermore, the ratio of CD4+/CD8+ T lymphocytes was significantly increased from 0.69 to 2.29 by treatment with DGVL. Immunoblotting analyses revealed that the expression of Fas and FasL on the thymus was lower in mice in the DGVL treatment group than in the control mice. In conclusion, DGVL can inhibit tumor growth and protect tumor-induced apoptosis of the thymus, and the mechanism is closely associated with reduced cell death in the thymus and a Fas-FasL-dependent pathway.
Zhao R et al; Can J Physiol Pharmacol. 89(9):665-73 (2011)
/ALTERNATIVE and IN VITRO TESTS/ The structure-activity relationships of flavonoids with regard to their inhibitory effects on phosphodiesterase (PDE) isozymes are little known. The activities of PDE1-5 were measured by a two-step procedure using cAMP with [(3)H]-cAMP or cGMP with [(3)H]-cGMP as substrates. In the present results, PDE1, 5, 2, and 4 isozymes were partially purified from guinea pig lungs in that order, and PDE3 was from the heart... Diosmetin more-selectively inhibited PDE2 (IC50) of 4.8 uM) than PDE1, PDE4, or PDE5... In conclusion, it is possible to synthesize useful drugs through elucidating the structure-activity relationships of flavonoids with respect to inhibition of PDE isozymes at concentrations used in this in vitro study.
Ko WC et al; Biochem Pharmacol 68 (10): 2087-94 (2004)
/ALTERNATIVE and IN VITRO TESTS/ This study/ evaluated the effects of increasing concentrations of the flavonoids salvigenin, diosmetin and luteolin on the in vitro metabolism of midazolam (MDZ), a probe substrate for cytochrome P450 (CYP) 3A enzymes, which is converted into 1'-hydroxy-midazolam (1'-OH-MDZ) and 4-hydroxy-midazolam (4-OH-MDZ) by human liver microsomes. Salvigenin had only a modest effect on MDZ metabolism, whereas diosmetin and luteolin inhibited in a concentration-dependent manner the formation of both 1'-OH-MDZ and 4-OH-MDZ, with apparent K(i) values in the 30-50 umol range. Both diosmetin and luteolin decreased 1'-OH-MDZ formation by human recombinant CYP3A4, but not CYP3A5, whereas they decreased 4-OH-MDZ formation by both recombinant enzymes. To assess whether any relationship exists between the physico-chemical characteristics of flavones and their effects on MDZ metabolism, /this study/ tested the effects of three other flavones (flavone, tangeretin, chrysin) on MDZ metabolism by human liver microsomes. Whereas flavones possessing more than two hydroxyl groups (luteolin, diosmetin) inhibited MDZ biotransformation, flavones lacking hydroxyl groups in their A and B rings (flavone, tangeretin) stimulated MDZ metabolism. /This study/ also found close relationships between the maximum stimulatory or inhibitory effects of flavones on 1'-OH-MDZ and 4-OH-MDZ formation rates and their log of octanol/water partition coefficients (logP) or their total number of hydroxyl groups. The results of the study may be of clinical relevance since they suggest that luteolin and diosmetin may cause pharmacokinetic interactions with co-administered drugs metabolized via CYP3A.
Quintieri L et al; Biochem Pharmacol 75(6): 1426-37 (2008)
For more Non-Human Toxicity Excerpts (Complete) data for Diosmetin (6 total), please visit the HSDB record page.

13.2 Ecological Information

13.2.1 Environmental Fate / Exposure Summary

Diosmetin's production and use in pharmacological, food and cosmetic research and as an intermediate and ingredient in food supplements and beverages may result in its release to the environment through various waste streams. Diosmetin is found naturally in citrus fruits and juices, such as orange juice, lemons, grapes and grapefruit. It also occurs in plants such as spearmint, oregano, sage, tansy, thyme and lemon. If released to air, an estimated vapor pressure of 3.8X10-12 mm Hg at 25 °C indicates diosmetin will exist solely in the particulate phase in the atmosphere. Particulate-phase diosmetin will be removed from the atmosphere by wet and dry deposition. If released to soil, diosmetin is expected to have low mobility based upon an estimated Koc of 2000. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 3.0X10-18 atm-cu m/mole. Diosmetin is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Diosmetin does contain chromophores that absorb at wavelengths >290 nm; therefore, it may be susceptible to direct photolysis on soil surfaces exposed to sunlight. Biodegradation data in soil or water were not available. If released into water, diosmetin is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 13 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Sensitized photo-oxidation may be an important fate process for diosmetin in natural waters exposed to sunlight. Occupational exposure to diosmetin may occur through dermal contact with this compound at workplaces where diosmetin is produced or used. The general population is exposed to diosmetin via ingestion of food, especially citrus fruits and juices, and dermal contact with this compound or other consumer products containing diosmetin. (SRC)

13.2.2 Natural Pollution Sources

Diosmetin has been identified in the following plants: Capsella bursa-pastoris (Shepherd's Purse plant), Citrus limon (lemon), Mentha spicata (spearmint plant), Origanum vulgare (oregano), Rosmarinus officinalis (rosemary plant), Salvia officinalis (sage), Salvia tomentosa (sage), Tanacetum vulgare (tansy plant), Thymus vulgaris (thyme plant)(1). Diosmetin is found naturally in citrus fruits and juices, such as orange juice, grapes and grapefruit(2).
(1) USDA; Dr. Duke's Phytochemical and Ethnobotanical Databases. Plants with a chosen chemical. Diosmetin. Washington, DC: US Dept Agric, Agric Res Service. Available from, as of Dec 25, 2012: https://www.ars-grin.gov/duke/
(2) RD; Right Diagnosis. Available from, as of Dec 25, 2012: https://www.rightdiagnosis.com/vitamin/diosmetin.htm

13.2.3 Artificial Pollution Sources

Diosmetin's production and use in pharmacological, food and cosmetic research and as an intermediate and ingredient in food supplements and beverages(1) may result in its release to the environment through various waste streams(SRC).
(1) Chem Faces; Chem Faces Biological Chemical Co Ltd., Product Information Datasheet. Diosmetin (CAS 520-34-3), Oct 2012. Available from, as of Dec 25, 2012: https://www.chemfaces.com/manual/Diosmetin-CFN90210.pdf

13.2.4 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2000(SRC), determined from a structure estimation method(2), indicates that diosmetin is expected to have low mobility in soil(SRC). Volatilization of diosmetin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.0X10-18 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Diosmetin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.8X10-12 mm Hg at 25 °C(SRC) determined from a fragment constant method(2). Diosmetin does contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis on soil surfaces exposed to sunlight(SRC).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.10. Jan, 2011. Available from, as of Dec 26, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-13 to 8-15 (1990)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2000(SRC), determined from a structure estimation method(2), indicates that diosmetin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 3.0X10-18 atm-cu m/mole(SRC) developed using a fragment constant estimation method(2). Phenols can undergo sensitized photo-oxidation in surface waters exposed to sunlight via reaction with hydroxyl and RO2 radicals with half-lives on the order of days to weeks at the water surface(4); therefore, photo-oxidation may be an important fate process for diosmetin in natural water(SRC). Diosmetin is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). Biodegradation data in water were not available(SRC, 2012).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.10. Jan, 2011. Available from, as of Dec 26, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 15-1 to 15-29 (1990)
(4) Mill T, Mabey W; p. 209 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), diosmetin, which has an estimated vapor pressure of 3.8X10-12 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase diosmetin may be removed from the air by wet and dry deposition(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.10. Jan, 2011. Available from, as of Dec 26, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

13.2.5 Environmental Abiotic Degradation

The rate constant for the vapor-phase reaction of diosmetin with photochemically-produced hydroxyl radicals has been estimated as 2.3X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 3 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Diosmetin is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Diosmetin does contain chromophores that absorb at wavelengths >290 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). Phenols can undergo sensitized photo-oxidation in surface waters exposed to sunlight via reaction with hydroxyl and RO2 radicals with half-lives on the order of days to weeks at the water surface(3); therefore, photo-oxidation may be an important fate process for diosmetin in natural water(SRC).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.10. Jan, 2011. Available from, as of Dec 26, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 8-13 to 8-15 (1990)
(3) Mill T, Mabey W; p. 209 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)

13.2.6 Environmental Bioconcentration

An estimated BCF of 13 was calculated in fish for diosmetin(SRC) using a log Kow of 3.10(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) Perrissoud D, Testa B; Arzneim-Forsch 36: 1249-1253 (1986)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.10. Jan, 2011. Available from, as of Dec 26, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

13.2.7 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of diosmetin can be estimated to be 2000(SRC). According to a classification scheme(2), this estimated Koc value suggests that diosmetin is expected to have low mobility in soil.
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.10. Jan, 2011. Available from, as of Dec 26, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(2) Swann RL et al; Res Rev 85: 17-28 (1983)

13.2.8 Volatilization from Water / Soil

The Henry's Law constant for diosmetin is estimated as 3.0X10-18 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that diosmetin is expected to be essentially nonvolatile from water surfaces(2). Diosmetin's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Diosmetin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.8X10-12 mm Hg(SRC) determined from a fragment constant method(1).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.10. Jan, 2011. Available from, as of Dec 26, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)

13.2.9 Food Survey Values

Diosmetin is found in citrus fruits and juices, such as orange juice, lemons, grapes and grapefruit(1).
(1) RD; Right Diagnosis. Available from, as of Dec 25, 2012: https://www.rightdiagnosis.com/vitamin/diosmetin.htm
Diosmetin has been extracted from the traditional Chinese herb Galium verum L.(1).
(1) Zhao R et al; Canadian J Phys Parm 89: 665-673 (2011)

13.2.10 Plant Concentrations

Diosmetin has been qualitatively identified in the following plants(1).
Genus species
Capsella bursa-pastoris
Common name
Shepard's Purse
Part
plant
Genus species
Citrus limon
Common name
Lemon
Part
plant
Genus species
Mentha spicata
Common name
Spearmint
Part
plant
Genus species
Origanum vulgare
Common name
Oregano
Part
plant
Genus species
Rosmarinus officinalis
Common name
Rosemary
Part
plant
Genus species
Salvia officinalis
Common name
Sage
Part
plant
Genus species
Salvia tomentosa
Common name
Sage
Part
plant
Genus species
Tanacetum vulgare
Common name
Tansy
Part
plant
Genus species
Thymus vulgaris
Common name
Thyme
Part
plant
(1) USDA; Dr. Duke's Phytochemical and Ethnobotanical Databases. Plants with a chosen chemical. Diosmetin. Washington, DC: US Dept Agric, Agric Res Service. Available from, as of Dec 25, 2012: https://www.ars-grin.gov/duke/
Diosmetin-6,8-di-C-glucoside was detected in Citrus suhuiensis peel, C. medica var 2 peel and C. medica var 2 flesh at concentrations of 4.72, 38 and 301 ug/g dry weight, respectively. Disometin -O-rutinoside was detected in C. hystrix leaf at 106 ng/g dry weight(1).
(1) Roowi S, Crozier A; J Agric Food Chem 59: 12217-25 (2011)

13.2.11 Average Daily Intake

Occupational exposure to diosmetin may occur through dermal contact with this compound at workplaces where diosmetin is produced or used. The general population is exposed to diosmetin via ingestion of food, especially citrus fruits and juices, and dermal contact with this compound or other consumer products containing diosmetin. (SRC)

14 Associated Disorders and Diseases

15 Literature

15.1 Consolidated References

15.2 NLM Curated PubMed Citations

15.3 Springer Nature References

15.4 Thieme References

15.5 Chemical Co-Occurrences in Literature

15.6 Chemical-Gene Co-Occurrences in Literature

15.7 Chemical-Disease Co-Occurrences in Literature

16 Patents

16.1 Depositor-Supplied Patent Identifiers

16.2 WIPO PATENTSCOPE

16.3 Chemical Co-Occurrences in Patents

16.4 Chemical-Disease Co-Occurrences in Patents

16.5 Chemical-Gene Co-Occurrences in Patents

17 Interactions and Pathways

17.1 Protein Bound 3D Structures

17.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

17.2 Chemical-Target Interactions

18 Biological Test Results

18.1 BioAssay Results

19 Taxonomy

The LOTUS Initiative for Open Natural Products Research: frozen dataset union wikidata (with metadata) | DOI:10.5281/zenodo.5794106

20 Classification

20.1 MeSH Tree

20.2 ChEBI Ontology

20.3 LIPID MAPS Classification

20.4 KEGG: Lipid

20.5 KEGG: Phytochemical Compounds

20.6 ChemIDplus

20.7 ChEMBL Target Tree

20.8 UN GHS Classification

20.9 EPA CPDat Classification

20.10 NORMAN Suspect List Exchange Classification

20.11 CCSBase Classification

20.12 EPA DSSTox Classification

20.13 LOTUS Tree

20.14 MolGenie Organic Chemistry Ontology

21 Information Sources

  1. BindingDB
    LICENSE
    All data curated by BindingDB staff are provided under the Creative Commons Attribution 3.0 License (https://creativecommons.org/licenses/by/3.0/us/).
    https://www.bindingdb.org/rwd/bind/info.jsp
    5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-chromen-4-one
    https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=23414
  2. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  3. Therapeutic Target Database (TTD)
  4. CAS Common Chemistry
    LICENSE
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    https://creativecommons.org/licenses/by-nc/4.0/
  5. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  6. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  7. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  8. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-benzopyrone
    https://chem.echa.europa.eu/100.007.539
    5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-benzopyrone (EC: 208-291-8)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/53630
  9. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  10. Hazardous Substances Data Bank (HSDB)
  11. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  12. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  13. ChEBI
  14. LOTUS - the natural products occurrence database
    LICENSE
    The code for LOTUS is released under the GNU General Public License v3.0.
    https://lotus.nprod.net/
  15. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  16. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    Diosmetin
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  17. DailyMed
  18. EPA Chemical and Products Database (CPDat)
  19. FooDB
    LICENSE
    FooDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (FooDB) and the original publication.
    https://foodb.ca/about
  20. Japan Chemical Substance Dictionary (Nikkaji)
  21. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
  22. KNApSAcK Species-Metabolite Database
  23. Natural Product Activity and Species Source (NPASS)
  24. LIPID MAPS
    Lipid Classification
    https://www.lipidmaps.org/
  25. MassBank Europe
  26. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  27. Metabolomics Workbench
  28. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  29. Protein Data Bank in Europe (PDBe)
  30. RCSB Protein Data Bank (RCSB PDB)
    LICENSE
    Data files contained in the PDB archive (ftp://ftp.wwpdb.org) are free of all copyright restrictions and made fully and freely available for both non-commercial and commercial use. Users of the data should attribute the original authors of that structural data.
    https://www.rcsb.org/pages/policies
  31. SpectraBase
    5,7,3'-TRIHYDROXY-4'-METHOXY-FLAVONE
    https://spectrabase.com/spectrum/A1m1vyJ9AHJ
    5,7,3'-Trihydroxy-4'-methoxy-flavone
    https://spectrabase.com/spectrum/DXicb0mCOem
  32. Springer Nature
  33. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  34. Wikidata
  35. Wikipedia
  36. PubChem
  37. Medical Subject Headings (MeSH)
    LICENSE
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    https://www.nlm.nih.gov/copyright.html
  38. GHS Classification (UNECE)
  39. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  40. PATENTSCOPE (WIPO)
CONTENTS