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Record Information
Version3.6
Creation Date2012-09-06 15:16:51 UTC
Update Date2016-02-11 01:32:29 UTC
HMDB IDHMDB15335
Secondary Accession NumbersNone
Metabolite Identification
Common NameMitoxantrone
DescriptionMitoxantrone is only found in individuals that have used or taken this drug. It is an anthracenedione-derived antineoplastic agent.Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity.
Structure
Thumb
Synonyms
ValueSource
1,4-DIHYDROXY-5,8-bis({2-[(2-hydroxyethyl)amino]ethyl}amino)-9,10-anthracenedioneChEBI
MitoxantronaChEBI
MitoxantronumChEBI
MitoxanthroneHMDB
MitoxantronHMDB
Chemical FormulaC22H28N4O6
Average Molecular Weight444.4809
Monoisotopic Molecular Weight444.200884648
IUPAC Name1,4-dihydroxy-5,8-bis({2-[(2-hydroxyethyl)amino]ethyl}amino)-9,10-dihydroanthracene-9,10-dione
Traditional Namemitoxantrone
CAS Registry Number65271-80-9
SMILES
OCCNCCNC1=C2C(=O)C3=C(O)C=CC(O)=C3C(=O)C2=C(NCCNCCO)C=C1
InChI Identifier
InChI=1S/C22H28N4O6/c27-11-9-23-5-7-25-13-1-2-14(26-8-6-24-10-12-28)18-17(13)21(31)19-15(29)3-4-16(30)20(19)22(18)32/h1-4,23-30H,5-12H2
InChI KeyInChIKey=KKZJGLLVHKMTCM-UHFFFAOYSA-N
Chemical Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as anthraquinones. These are organic compounds containing either anthracene-9,10-quinone, 1,4-anthraquinone, or 1,2-anthraquinone.
KingdomOrganic compounds
Super ClassBenzenoids
ClassAnthracenes
Sub ClassAnthraquinones
Direct ParentAnthraquinones
Alternative Parents
Substituents
  • Anthraquinone
  • 9,10-anthraquinone
  • Aryl ketone
  • Hydroquinone
  • Secondary aliphatic/aromatic amine
  • Vinylogous amide
  • Vinylogous acid
  • Ketone
  • 1,2-aminoalcohol
  • Secondary amine
  • Secondary aliphatic amine
  • Alkanolamine
  • Hydrocarbon derivative
  • Primary alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Alcohol
  • Aromatic homopolycyclic compound
Molecular FrameworkAromatic homopolycyclic compounds
External Descriptors
Ontology
StatusExpected but not Quantified
Origin
  • Drug
Biofunction
  • Analgesics
  • Antineoplastic Agents
Application
  • Pharmaceutical
Cellular locations
  • Cytoplasm
  • Membrane
Physical Properties
StateLiquid
Experimental Properties
PropertyValueReference
Melting PointNot AvailableNot Available
Boiling PointNot AvailableNot Available
Water Solubility7.34e-01 g/LNot Available
LogP-3.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.73 mg/mLALOGPS
logP0.91ALOGPS
logP1.19ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)9.78ChemAxon
pKa (Strongest Basic)9.08ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count8ChemAxon
Polar Surface Area163.18 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity123.53 m3·mol-1ChemAxon
Polarizability48.49 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Biological Properties
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid Locations
  • Blood
  • Urine
Tissue LocationNot Available
PathwaysNot Available
Normal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodExpected but not QuantifiedNot ApplicableNot AvailableNot AvailableTaking drug identified by DrugBank entry DB01204
  • Not Applicable
details
UrineExpected but not QuantifiedNot ApplicableNot AvailableNot AvailableTaking drug identified by DrugBank entry DB01204
  • Not Applicable
details
Abnormal Concentrations
Not Available
Predicted Concentrations
BiofluidValueOriginal ageOriginal sexOriginal conditionComments
Blood0-2 uMAdult (>18 years old)BothNormalPredicted based on drug qualities
Blood0-1 umol/mmol creatinineAdult (>18 years old)BothNormalPredicted based on drug qualities
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDDB01204
DrugBank Metabolite IDNot Available
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDNot Available
KNApSAcK IDNot Available
Chemspider ID4067
KEGG Compound IDC11195
BioCyc IDNot Available
BiGG IDNot Available
Wikipedia LinkMitoxantrone
NuGOwiki LinkHMDB15335
Metagene LinkHMDB15335
METLIN IDNot Available
PubChem Compound4212
PDB IDMIX
ChEBI ID50729
References
Synthesis ReferenceNot Available
Material Safety Data Sheet (MSDS)Not Available
General References
  1. Fox EJ: Management of worsening multiple sclerosis with mitoxantrone: a review. Clin Ther. 2006 Apr;28(4):461-74. [16750460 ]

Enzymes

General function:
Involved in monooxygenase activity
Specific function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular weight:
57255.585
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. [19934256 ]
General function:
Involved in monooxygenase activity
Specific function:
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms.
Gene Name:
CYP2E1
Uniprot ID:
P05181
Molecular weight:
56848.42
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. [19934256 ]
General function:
Involved in monooxygenase activity
Specific function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Participates in the metabolism of an as-yet-unknown biologically active molecule that is a participant in eye development.
Gene Name:
CYP1B1
Uniprot ID:
Q16678
Molecular weight:
60845.33
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. [19934256 ]
General function:
Involved in sequence-specific DNA binding transcription factor activity
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:
TOP2A
Uniprot ID:
P11388
Molecular weight:
174383.9
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Takeda K, Shinohara K, Kameda N, Ariyoshi K: A case of therapy-related acute myeloblastic leukemia with t(16;21)(q24;q22) after chemotherapy with DNA-topoisomerase II inhibitors, etoposide and mitoxantrone, and the alkylating agent, cyclophosphamide. Int J Hematol. 1998 Feb;67(2):179-86. [9631585 ]
  3. McPherson JP, Deffie AM, Jones NR, Brown GA, Deuchars KL, Goldenberg GJ: Selective sensitization of adriamycin-resistant P388 murine leukemia cells to antineoplastic agents following transfection with human DNA topoisomerase II alpha. Anticancer Res. 1997 Nov-Dec;17(6D):4243-52. [9494516 ]
  4. Wang H, Mao Y, Zhou N, Hu T, Hsieh TS, Liu LF: Atp-bound topoisomerase ii as a target for antitumor drugs. J Biol Chem. 2001 May 11;276(19):15990-5. Epub 2001 Feb 23. [11278845 ]
  5. Satherley K, de Souza L, Neale MH, Alexander RA, Myatt N, Foss AJ, Hungerford JL, Hickson ID, Cree IA: Relationship between expression of topoisomerase II isoforms and chemosensitivity in choroidal melanoma. J Pathol. 2000 Oct;192(2):174-81. [11004693 ]
  6. Mao Y, Yu C, Hsieh TS, Nitiss JL, Liu AA, Wang H, Liu LF: Mutations of human topoisomerase II alpha affecting multidrug resistance and sensitivity. Biochemistry. 1999 Aug 17;38(33):10793-800. [10451375 ]
  7. Ko MW, Tamhankar MA, Volpe NJ, Porter D, McGrath C, Galetta SL: Acute promyelocytic leukemic involvement of the optic nerves following mitoxantrone treatment for multiple sclerosis. J Neurol Sci. 2008 Oct 15;273(1-2):144-7. Epub 2008 Aug 6. [18687447 ]

Transporters

General function:
Involved in ATP binding
Specific function:
Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o- glucuronide, methotrexate, antiviral drugs and other xenobiotics. Confers resistance to anticancer drugs. Hydrolyzes ATP with low efficiency
Gene Name:
ABCC1
Uniprot ID:
P33527
Molecular weight:
171589.5
References
  1. Morrow CS, Peklak-Scott C, Bishwokarma B, Kute TE, Smitherman PK, Townsend AJ: Multidrug resistance protein 1 (MRP1, ABCC1) mediates resistance to mitoxantrone via glutathione-dependent drug efflux. Mol Pharmacol. 2006 Apr;69(4):1499-505. Epub 2006 Jan 24. [16434618 ]
  2. Diah SK, Smitherman PK, Aldridge J, Volk EL, Schneider E, Townsend AJ, Morrow CS: Resistance to mitoxantrone in multidrug-resistant MCF7 breast cancer cells: evaluation of mitoxantrone transport and the role of multidrug resistance protein family proteins. Cancer Res. 2001 Jul 15;61(14):5461-7. [11454692 ]
General function:
Involved in ATP binding
Specific function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular weight:
141477.3
References
  1. Schrenk D, Michalke A, Gant TW, Brown PC, Silverman JA, Thorgeirsson SS: Multidrug resistance gene expression in rodents and rodent hepatocytes treated with mitoxantrone. Biochem Pharmacol. 1996 Nov 8;52(9):1453-60. [8937457 ]
  2. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS: Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001 Nov;299(2):620-8. [11602674 ]
  3. Taipalensuu J, Tavelin S, Lazorova L, Svensson AC, Artursson P: Exploring the quantitative relationship between the level of MDR1 transcript, protein and function using digoxin as a marker of MDR1-dependent drug efflux activity. Eur J Pharm Sci. 2004 Jan;21(1):69-75. [14706813 ]
  4. Noguchi K, Kawahara H, Kaji A, Katayama K, Mitsuhashi J, Sugimoto Y: Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib. Cancer Sci. 2009 Sep;100(9):1701-7. Epub 2009 May 12. [19493273 ]
General function:
Involved in ATP binding
Specific function:
Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. May be involved in brain-to-blood efflux. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. When overexpressed, the transfected cells become resistant to mitoxantrone, daunorubicin and doxorubicin, display diminished intracellular accumulation of daunorubicin, and manifest an ATP- dependent increase in the efflux of rhodamine 123
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
Molecular weight:
72313.5
References
  1. Volk EL, Schneider E: Wild-type breast cancer resistance protein (BCRP/ABCG2) is a methotrexate polyglutamate transporter. Cancer Res. 2003 Sep 1;63(17):5538-43. [14500392 ]
  2. Elahian F, Kalalinia F, Behravan J: Evaluation of indomethacin and dexamethasone effects on BCRP-mediated drug resistance in MCF-7 parental and resistant cell lines. Drug Chem Toxicol. 2010 Apr;33(2):113-9. [20307139 ]
  3. Morrow CS, Peklak-Scott C, Bishwokarma B, Kute TE, Smitherman PK, Townsend AJ: Multidrug resistance protein 1 (MRP1, ABCC1) mediates resistance to mitoxantrone via glutathione-dependent drug efflux. Mol Pharmacol. 2006 Apr;69(4):1499-505. Epub 2006 Jan 24. [16434618 ]
  4. Litman T, Brangi M, Hudson E, Fetsch P, Abati A, Ross DD, Miyake K, Resau JH, Bates SE: The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2). J Cell Sci. 2000 Jun;113 ( Pt 11):2011-21. [10806112 ]
  5. Wang X, Furukawa T, Nitanda T, Okamoto M, Sugimoto Y, Akiyama S, Baba M: Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. Mol Pharmacol. 2003 Jan;63(1):65-72. [12488537 ]
  6. Sugimoto Y, Tsukahara S, Imai Y, Sugimoto Y, Ueda K, Tsuruo T: Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists. Mol Cancer Ther. 2003 Jan;2(1):105-12. [12533678 ]
  7. Maliepaard M, van Gastelen MA, de Jong LA, Pluim D, van Waardenburg RC, Ruevekamp-Helmers MC, Floot BG, Schellens JH: Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res. 1999 Sep 15;59(18):4559-63. [10493507 ]
  8. Ozvegy C, Litman T, Szakacs G, Nagy Z, Bates S, Varadi A, Sarkadi B: Functional characterization of the human multidrug transporter, ABCG2, expressed in insect cells. Biochem Biophys Res Commun. 2001 Jul 6;285(1):111-7. [11437380 ]
  9. Imai Y, Asada S, Tsukahara S, Ishikawa E, Tsuruo T, Sugimoto Y: Breast cancer resistance protein exports sulfated estrogens but not free estrogens. Mol Pharmacol. 2003 Sep;64(3):610-8. [12920197 ]
  10. Miwa M, Tsukahara S, Ishikawa E, Asada S, Imai Y, Sugimoto Y: Single amino acid substitutions in the transmembrane domains of breast cancer resistance protein (BCRP) alter cross resistance patterns in transfectants. Int J Cancer. 2003 Dec 10;107(5):757-63. [14566825 ]
  11. Nakanishi T, Doyle LA, Hassel B, Wei Y, Bauer KS, Wu S, Pumplin DW, Fang HB, Ross DD: Functional characterization of human breast cancer resistance protein (BCRP, ABCG2) expressed in the oocytes of Xenopus laevis. Mol Pharmacol. 2003 Dec;64(6):1452-62. [14645676 ]
  12. Allen JD, Van Dort SC, Buitelaar M, van Tellingen O, Schinkel AH: Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein. Cancer Res. 2003 Mar 15;63(6):1339-44. [12649196 ]
  13. Allen JD, Brinkhuis RF, Wijnholds J, Schinkel AH: The mouse Bcrp1/Mxr/Abcp gene: amplification and overexpression in cell lines selected for resistance to topotecan, mitoxantrone, or doxorubicin. Cancer Res. 1999 Sep 1;59(17):4237-41. [10485464 ]
  14. An Y, Ongkeko WM: ABCG2: the key to chemoresistance in cancer stem cells? Expert Opin Drug Metab Toxicol. 2009 Dec;5(12):1529-42. [19708828 ]
  15. Paturi DK, Kwatra D, Ananthula HK, Pal D, Mitra AK: Identification and functional characterization of breast cancer resistance protein in human bronchial epithelial cells (Calu-3). Int J Pharm. 2010 Jan 15;384(1-2):32-8. Epub 2009 Sep 25. [19782742 ]
  16. Ma Y, Wink M: The beta-carboline alkaloid harmine inhibits BCRP and can reverse resistance to the anticancer drugs mitoxantrone and camptothecin in breast cancer cells. Phytother Res. 2010 Jan;24(1):146-9. [19548284 ]
  17. Mahringer A, Delzer J, Fricker G: A fluorescence-based in vitro assay for drug interactions with breast cancer resistance protein (BCRP, ABCG2). Eur J Pharm Biopharm. 2009 Aug;72(3):605-13. [19572416 ]
  18. Nicolle E, Boccard J, Guilet D, Dijoux-Franca MG, Zelefac F, Macalou S, Grosselin J, Schmidt J, Carrupt PA, Di Pietro A, Boumendjel A: Breast cancer resistance protein (BCRP/ABCG2): new inhibitors and QSAR studies by a 3D linear solvation energy approach. Eur J Pharm Sci. 2009 Aug 12;38(1):39-46. Epub 2009 Jun 6. [19501160 ]
  19. Jani M, Szabo P, Kis E, Molnar E, Glavinas H, Krajcsi P: Kinetic characterization of sulfasalazine transport by human ATP-binding cassette G2. Biol Pharm Bull. 2009 Mar;32(3):497-9. [19252303 ]
  20. Karla PK, Earla R, Boddu SH, Johnston TP, Pal D, Mitra A: Molecular expression and functional evidence of a drug efflux pump (BCRP) in human corneal epithelial cells. Curr Eye Res. 2009 Jan;34(1):1-9. [19172464 ]
  21. Tiwari AK, Sodani K, Wang SR, Kuang YH, Ashby CR Jr, Chen X, Chen ZS: Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem Pharmacol. 2009 Jul 15;78(2):153-61. Epub 2009 Apr 11. [19427995 ]
  22. Noguchi K, Kawahara H, Kaji A, Katayama K, Mitsuhashi J, Sugimoto Y: Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib. Cancer Sci. 2009 Sep;100(9):1701-7. Epub 2009 May 12. [19493273 ]
  23. Shi Z, Parmar S, Peng XX, Shen T, Robey RW, Bates SE, Fu LW, Shao Y, Chen YM, Zang F, Chen ZS: The epidermal growth factor tyrosine kinase inhibitor AG1478 and erlotinib reverse ABCG2-mediated drug resistance. Oncol Rep. 2009 Feb;21(2):483-9. [19148526 ]
  24. Ross DD, Yang W, Abruzzo LV, Dalton WS, Schneider E, Lage H, Dietel M, Greenberger L, Cole SP, Doyle LA: Atypical multidrug resistance: breast cancer resistance protein messenger RNA expression in mitoxantrone-selected cell lines. J Natl Cancer Inst. 1999 Mar 3;91(5):429-33. [10070941 ]
  25. Brangi M, Litman T, Ciotti M, Nishiyama K, Kohlhagen G, Takimoto C, Robey R, Pommier Y, Fojo T, Bates SE: Camptothecin resistance: role of the ATP-binding cassette (ABC), mitoxantrone-resistance half-transporter (MXR), and potential for glucuronidation in MXR-expressing cells. Cancer Res. 1999 Dec 1;59(23):5938-46. [10606239 ]
  26. Rocchi E, Khodjakov A, Volk EL, Yang CH, Litman T, Bates SE, Schneider E: The product of the ABC half-transporter gene ABCG2 (BCRP/MXR/ABCP) is expressed in the plasma membrane. Biochem Biophys Res Commun. 2000 Apr 29;271(1):42-6. [10777678 ]
  27. Jonker JW, Smit JW, Brinkhuis RF, Maliepaard M, Beijnen JH, Schellens JH, Schinkel AH: Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst. 2000 Oct 18;92(20):1651-6. [11036110 ]