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Record Information
Version2.0
Creation Date2014-09-11 02:05:21 UTC
Update Date2014-12-24 20:26:55 UTC
Accession NumberT3D4695
Identification
Common NameEtoposide
ClassSmall Molecule
DescriptionA semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.
Compound Type
  • Antineoplastic Agent, Phytogenic
  • Drug
  • Ester
  • Ether
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(-)-Etoposide
4'-Demethylepipodophyllotoxin 9-(4,6-O-(R)-ethylidene-beta-D-glucopyranoside)
4-Demethylepipodophyllotoxin beta-D-ethylideneglucoside
9-((4,6-O-Ethylidine-beta-D-glucopyranosyl)oxy)-5,8,8a,9-tetrahydro-5-(4-hydroxy-3,4-dimethyloxyphenyl)furo(3',4'':6,7)naptho-(2,3-D)-1,3-dioxol-6(5ah)-one
EPE
EPEG
Epipodophyllotoxin
Eposin
Etopofos
Etopophos
Etoposid
Etoposido
Etoposidum
Lastet
Nexvep
Toposar
trans-Etoposide
Vepesid
Vepesid K
Vépéside
VP-16
Chemical FormulaC29H32O13
Average Molecular Mass588.557 g/mol
Monoisotopic Mass588.184 g/mol
CAS Registry Number33419-42-0
IUPAC Name(10R,11R,15R,16S)-16-{[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-hexahydro-2H-pyrano[3,2-d][1,3]dioxin-6-yl]oxy}-10-(4-hydroxy-3,5-dimethoxyphenyl)-4,6,13-trioxatetracyclo[7.7.0.0^{3,7}.0^{11,15}]hexadeca-1,3(7),8-trien-12-one
Traditional Name(10R,11R,15R,16S)-16-{[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-hexahydro-2H-pyrano[3,2-d][1,3]dioxin-6-yl]oxy}-10-(4-hydroxy-3,5-dimethoxyphenyl)-4,6,13-trioxatetracyclo[7.7.0.0^{3,7}.0^{11,15}]hexadeca-1,3(7),8-trien-12-one
SMILES[H][C@]12COC(=O)[C@]1([H])[C@]([H])(C1=CC(OC)=C(O)C(OC)=C1)C1=CC3=C(OCO3)C=C1[C@@]2([H])O[C@]1([H])O[C@]2([H])CO[C@@]([H])(C)O[C@@]2([H])[C@]([H])(O)[C@@]1([H])O
InChI IdentifierInChI=1S/C29H32O13/c1-11-36-9-20-27(40-11)24(31)25(32)29(41-20)42-26-14-7-17-16(38-10-39-17)6-13(14)21(22-15(26)8-37-28(22)33)12-4-18(34-2)23(30)19(5-12)35-3/h4-7,11,15,20-22,24-27,29-32H,8-10H2,1-3H3/t11-,15+,20-,21-,22+,24-,25-,26-,27-,29+/m1/s1
InChI KeyInChIKey=VJJPUSNTGOMMGY-MRVIYFEKSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as tetrahydroisoquinolines. These are tetrahydrogenated isoquinoline derivatives.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassTetrahydroisoquinolines
Sub ClassNot Available
Direct ParentTetrahydroisoquinolines
Alternative Parents
Substituents
  • Tetrahydroisoquinoline
  • 3-piperidinecarboxamide
  • Piperidinecarboxamide
  • Anisole
  • Alkyl aryl ether
  • Aralkylamine
  • Benzenoid
  • Piperidine
  • Tertiary carboxylic acid amide
  • Tertiary aliphatic amine
  • Amino acid or derivatives
  • Tertiary amine
  • Carboxamide group
  • Carboxylic acid ester
  • Azacycle
  • Carboxylic acid derivative
  • Ether
  • Monocarboxylic acid or derivatives
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Organooxygen compound
  • Organic oxygen compound
  • Organopnictogen compound
  • Carbonyl group
  • Organic nitrogen compound
  • Organic oxide
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point236 - 251°C
Boiling PointNot Available
Solubility9.78e-01 g/L
LogP0.6
Predicted Properties
PropertyValueSource
Water Solubility0.98 g/LALOGPS
logP0.73ALOGPS
logP1.16ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)9.33ChemAxon
pKa (Strongest Basic)-3.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area160.83 ŲChemAxon
Rotatable Bond Count5ChemAxon
Refractivity139.02 m³·mol⁻¹ChemAxon
Polarizability57.95 ųChemAxon
Number of Rings7ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0bvi-1901070000-74ac7d5d623bed96366eJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-0mm1-2900107000-099107e3dc57314671efJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS ("Etoposide,1TMS,#1" TMS) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_2) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_3) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_2_1) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_2_2) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_2_3) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_3_1) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_1_1) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_1_2) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_1_3) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_2_1) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_2_2) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_2_3) - 70eV, PositiveNot AvailableJSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-004r-0690000000-25202a61d19d3dfaed8bJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-004r-0090420000-e5d6bcd633116e0553a0JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-004i-0190000000-ac64a57347a9295be5dcJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-004r-0590000000-e0e45774111103754c46JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-002r-0980000000-ccf595459b4b1988d77aJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-002r-0950000000-4d3313053107615d463aJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 30V, Positivesplash10-004r-0590000000-e653736b252cc5e2e795JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 40V, Positivesplash10-002r-0980000000-48f8ee63240c179183f6JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 10V, Positivesplash10-004r-0090420000-4257cbcff5646216f202JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 6V, Positivesplash10-004r-0590000000-8c7420414be0c3746affJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 6V, Positivesplash10-002r-0091540000-94d46ba9cac17da0c456JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 40V, Positivesplash10-000i-0930000000-d9d8244725f2e57fce96JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 35V, Negativesplash10-0019-0397150000-e467d625bbc856208c08JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 6V, Positivesplash10-000i-0930000000-2f7ed12e16b6771697e6JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 6V, Positivesplash10-004i-0290010000-9da8eeb575b398d3bdbdJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 6V, Positivesplash10-000i-0930000000-d15ca68c1981073da181JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 50V, Positivesplash10-002r-0950000000-4d3313053107615d463aJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 35V, Positivesplash10-004i-0390000000-b642957170b052134776JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 10V, Positivesplash10-002r-0091670000-9a34ca7c7757308b4693JSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0uei-0106690000-bd98e3ad1ce23f0413c0JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0ue9-0119510000-51cff21db98c0ed7effdJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0ue9-0219300000-8bb469d4a7eadf8f5308JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-000j-1306090000-5791526d6f416ac328bfJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-000t-2009030000-3ed5cbe07a1ce3f87bf6JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-000t-2009000000-41d7c2765f3c44df7f34JSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
Toxicity Profile
Route of ExposureAbsorbed well, time to peak plasma concentration is 1-1.5 hrs. Mean bioavailability is 50% (range of 25% - 75%). Cmax and AUC values for orally administered etoposide capsules display intra- and inter-subject variability. There is no evidence of first-pass effect for etoposide.
Mechanism of ToxicityEtoposide inhibits DNA topoisomerase II, thereby inhibiting DNA re-ligation. This causes critical errors in DNA synthesis at the premitotic stage of cell division and can lead to apoptosis of the cancer cell. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases of cell division. Inhibition of the topoisomerase II alpha isoform results in the anti-tumour activity of etoposide. The drug is also capable of inhibiting the beta isoform but inhibition of this target is not associated with the anti-tumour activity. It is instead associated with the carcinogenic effect.
MetabolismPrimarily hepatic (through O-demethylation via the CYP450 3A4 isoenzyme pathway) with 40% excreted unchanged in the urine. Etoposide also undergoes glutathione and glucuronide conjugation which are catalyzed by GSTT1/GSTP1 and UGT1A1, respectively. Prostaglandin synthases are also responsible for the conversion of etoposide to O-demethylated metabolites (quinone). Route of Elimination: Etoposide is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous dose. 56% of the dose was in the urine, 45% of which was excreted as etoposide. Half Life: 4-11 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)1, carcinogenic to humans. (3)
Uses/SourcesFor use in combination with other chemotherapeutic agents in the treatment of refractory testicular tumors and as first line treatment in patients with small cell lung cancer. Also used to treat other malignancies such as lymphoma, non-lymphocytic leukemia, and glioblastoma multiforme.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsSide effects include alopecia, constipation, diarrhea, nausea and vomiting and secondary malignancies (leukemia).
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00773
HMDB IDHMDB14911
PubChem Compound ID36462
ChEMBL IDCHEMBL44657
ChemSpider ID33510
KEGG IDC01576
UniProt IDNot Available
OMIM ID
ChEBI ID4911
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDEVP
ACToR IDNot Available
Wikipedia LinkEtoposide
References
Synthesis Reference

DrugSyn.org

MSDSLink
General References
  1. Zhou Z, Zwelling LA, Ganapathi R, Kleinerman ES: Enhanced etoposide sensitivity following adenovirus-mediated human topoisomerase IIalpha gene transfer is independent of topoisomerase IIbeta. Br J Cancer. 2001 Sep 1;85(5):747-51. [11531262 ]
  2. Azarova AM, Lyu YL, Lin CP, Tsai YC, Lau JY, Wang JC, Liu LF: Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11014-9. Epub 2007 Jun 19. [17578914 ]
  3. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Ubiquitin binding
Specific Function:
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes. May play a role in regulating the period length of ARNTL/BMAL1 transcriptional oscillation (By similarity).
Gene Name:
TOP2A
Uniprot ID:
P11388
Molecular Weight:
174383.88 Da
References
  1. de Lucio B, Manuel V, Barrera-Rodriguez R: Characterization of human NSCLC cell line with innate etoposide-resistance mediated by cytoplasmic localization of topoisomerase II alpha. Cancer Sci. 2005 Nov;96(11):774-83. [16271071 ]
  2. Lopez-Lazaro M, Pastor N, Azrak SS, Ayuso MJ, Austin CA, Cortes F: Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients. J Nat Prod. 2005 Nov;68(11):1642-5. [16309315 ]
  3. Moneypenny CG, Shao J, Song Y, Gallagher EP: MLL rearrangements are induced by low doses of etoposide in human fetal hematopoietic stem cells. Carcinogenesis. 2006 Apr;27(4):874-81. Epub 2005 Dec 24. [16377807 ]
  4. Uesaka T, Shono T, Kuga D, Suzuki SO, Niiro H, Miyamoto K, Matsumoto K, Mizoguchi M, Ohta M, Iwaki T, Sasaki T: Enhanced expression of DNA topoisomerase II genes in human medulloblastoma and its possible association with etoposide sensitivity. J Neurooncol. 2007 Sep;84(2):119-29. Epub 2007 Mar 15. [17361331 ]
  5. Winnicka K, Bielawski K, Bielawska A: Cardiac glycosides in cancer research and cancer therapy. Acta Pol Pharm. 2006 Mar-Apr;63(2):109-15. [17514873 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
General Function:
Protein kinase c binding
Specific Function:
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks.
Gene Name:
TOP2B
Uniprot ID:
Q02880
Molecular Weight:
183265.825 Da
References
  1. Azarova AM, Lyu YL, Lin CP, Tsai YC, Lau JY, Wang JC, Liu LF: Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11014-9. Epub 2007 Jun 19. [17578914 ]