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Record Information
Version2.0
Creation Date2009-07-30 17:58:57 UTC
Update Date2014-12-24 20:26:07 UTC
Accession NumberT3D3513
Identification
Common NameIfosfamide
ClassSmall Molecule
DescriptionIfosfamide is a chemotherapeutic agent chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide. It is active as an alkylating agent and an immunosuppresive agent. The exact mechanism of ifosfamide has not been determined, but appears to be similar to other alkylating agents. Ifosfamide requires biotransformation in the liver by mixed-function oxidases (cytochrome P450 system) before it becomes active. After metabolic activation, active metabolites of ifosfamide alkylate or bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily through the alkylation of DNA, done by attaching the N-7 position of guanine to its reactive electrophilic groups. The formation of inter and intra strand cross-links in the DNA results in cell death.
Compound Type
  • Amide
  • Antineoplastic Agent
  • Antineoplastic Agent, Alkylating
  • Drug
  • Ester
  • Immunosuppressive Agent
  • Metabolite
  • Organic Compound
  • Organochloride
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
3-(2-Chloroethyl)-2-((2-chloroethyl)amino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide
Asta Z 4942
Celofos
Cuantil
Holoxan
I-Phosphamide
Ifex
Ifosfamid
Ifosfamida
Ifosfamide Sterile
Ifosfamidum
Ifosphamide
Ifsofamide
Iphosphamid
Iphosphamide
Isofosfamide
Isophosphamide
Isosfamide
Mitoxana
Chemical FormulaC7H15Cl2N2O2P
Average Molecular Mass261.086 g/mol
Monoisotopic Mass260.025 g/mol
CAS Registry Number3778-73-2
IUPAC Name3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-1,3,2lambda5-oxazaphosphinan-2-one
Traditional Name3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-1,3,2lambda5-oxazaphosphinan-2-one
SMILESClCCNP1(=O)OCCCN1CCCl
InChI IdentifierInChI=1/C7H15Cl2N2O2P/c8-2-4-10-14(12)11(6-3-9)5-1-7-13-14/h1-7H2,(H,10,12)
InChI KeyInChIKey=HOMGKSMUEGBAAB-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as isofamides. These are oxazaphospholanes containing the isofamide skeleton. Isofamide is a heterocyclic compound made up of a 1,3,2-oxazaphospholane, where the phosphorus atom is part of a phosphodiamide group, and the oxazaphospholane is substituted by two haloalkyl chains.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassOxazaphosphinanes
Sub ClassIsofamides
Direct ParentIsofamides
Alternative Parents
Substituents
  • Isofamide
  • Phosphoric monoester diamide
  • Organic phosphoric acid derivative
  • Organic phosphoric acid amide
  • Azacycle
  • Oxacycle
  • Alkyl chloride
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organic oxygen compound
  • Organohalogen compound
  • Organic nitrogen compound
  • Alkyl halide
  • Aliphatic heteromonocyclic compound
Molecular FrameworkAliphatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point39-41°C
Boiling PointNot Available
Solubility3780 mg/L
LogP0.86
Predicted Properties
PropertyValueSource
Water Solubility15 g/LALOGPS
logP0.57ALOGPS
logP0.097ChemAxon
logS-1.2ALOGPS
pKa (Strongest Acidic)14.59ChemAxon
pKa (Strongest Basic)-0.03ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area41.57 ŲChemAxon
Rotatable Bond Count5ChemAxon
Refractivity58.48 m³·mol⁻¹ChemAxon
Polarizability23.94 ųChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
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, Positivesplash10-03gj-3950000000-d61f04c75e5216d6c481JSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-001i-0290000000-4c400c6848932e5bc304JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-03di-1390000000-cb6bb34e3efac3f15b24JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-0udi-3910000000-2729bcf5701a78198ad5JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-001i-0490000000-17ba12fd0e00df2723dcJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-03di-0090000000-d4e1a660175509162e8cJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-03di-0090000000-c26cb9c6b0b1cafbc7c2JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0gx3-6960000000-e4f4eadda4e355e7dd84JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0f6x-8900000000-10d5b2623785719eb1e7JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0006-9500000000-d06de43b506b64b21f31JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0006-9300000000-698d7a6ed4f1837ad721JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-03di-0090000000-084cc16ffb95bd0ef960JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-03di-0090000000-1ae1b6f01a6e1a37e34cJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0gx3-6960000000-ad40c4b969e8d0286677JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0f6x-8900000000-137610f53c637d8d5b79JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0006-9500000000-6b78178980477a0f7c08JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0006-9200000000-e6f6b95f30fc4c9fde8aJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-001i-0490000000-661cabcd304902a3d4b5JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-001i-0290000000-4c400c6848932e5bc304JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-03di-1390000000-cb6bb34e3efac3f15b24JSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0006-9030000000-82608eec100a23f0266eJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-001i-9100000000-755c8d4c9c0f9d89400eJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0006-9000000000-8b8aed41746e222fd47aJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0002-1910000000-ddc3d173bfc120e5f7dcJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0159-8900000000-e4192b3d1839133ffa5eJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-004i-9000000000-7de8be0f841d92b19769JSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
Toxicity Profile
Route of ExposureIntravenous injection
Mechanism of ToxicityAfter metabolic activation, active metabolites of ifosfamide alkylate or bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily due to cross-linking of strands of DNA and RNA, as well as inhibition of protein synthesis.
MetabolismPrimarily hepatic. Ifosfamide is metabolized through two metabolic pathways: ring oxidation ("activation") to form the active metabolite, 4-hydroxy-ifosfamide and side-chain oxidation to form the inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide with liberation of the toxic metabolite, chloroacetaldehyde. Small quantities (nmol/mL) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma. Metabolism of ifosfamide is required for the generation of the biologically active species and while metabolism is extensive, it is also quite variable among patients. Route of Elimination: Ifosfamide is extensively metabolized in humans and the metabolic pathways appear to be saturated at high doses. After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in the urine, with about 61% of the dose excreted as parent compound. At doses of 1.6 - 2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours. Half Life: 7-15 hours. The elimination half-life increase appeared to be related to the increase in ifosfamide volume of distribution with age.
Toxicity ValuesLD50 (mouse) = 390-1005 mg/kg, LD50 (rat) = 150-190 mg/kg.
Lethal DoseNot Available
Carcinogenicity (IARC Classification)3, not classifiable as to its carcinogenicity to humans. (13)
Uses/SourcesUsed as a component of various chemotherapeutic regimens as third-line therapy for recurrent or refractory germ cell testicular cancer. Also used as a component of various chemotherapeutic regimens for the treatment of cervical cancer, as well as in conjunction with surgery and/or radiation therapy in the treatment of various soft tissue sarcomas. Other indications include treatment of osteosarcoma, bladder cancer, ovarian cancer. small cell lung cancer, and non-Hodgkin's lymphoma.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsSide effects include nausea, vomiting and myelosuppression. Toxic effects include central nervous system toxicity (confusion, hallucinations) and urotoxic effects (cystitis, blood in urine).
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01181
HMDB IDHMDB15312
PubChem Compound ID3690
ChEMBL IDCHEMBL1024
ChemSpider ID3562
KEGG IDC07047
UniProt IDNot Available
OMIM ID
ChEBI ID5864
BioCyc IDNot Available
CTD IDNot Available
Stitch IDIfosfamide
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkIfosfamide
References
Synthesis Reference

U.S. Patent 3,732,340.

MSDSLink
General References
  1. Furlanut M, Franceschi L: Pharmacology of ifosfamide. Oncology. 2003;65 Suppl 2:2-6. [14586139 ]
  2. Fleming RA: An overview of cyclophosphamide and ifosfamide pharmacology. Pharmacotherapy. 1997 Sep-Oct;17(5 Pt 2):146S-154S. [9322882 ]
  3. Wagner T: Ifosfamide clinical pharmacokinetics. Clin Pharmacokinet. 1994 Jun;26(6):439-56. [8070218 ]
  4. Allen LM, Creaven PJ, Nelson RL: Studies on the human pharmacokinetics of isophosphamide (NSC-109724). Cancer Treat Rep. 1976 Apr;60(4):451-8. [1277221 ]
  5. Brade WP, Herdrich K, Varini M: Ifosfamide--pharmacology, safety and therapeutic potential. Cancer Treat Rev. 1985 Mar;12(1):1-47. [3896483 ]
  6. Zalupski M, Baker LH: Ifosfamide. J Natl Cancer Inst. 1988 Jun 15;80(8):556-66. [3286879 ]
  7. Willits I, Price L, Parry A, Tilby MJ, Ford D, Cholerton S, Pearson AD, Boddy AV: Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer. Br J Cancer. 2005 May 9;92(9):1626-35. [15827549 ]
  8. Lokiec F: Ifosfamide: pharmacokinetic properties for central nervous system metastasis prevention. Ann Oncol. 2006 May;17 Suppl 4:iv33-6. [16702183 ]
  9. Schoenike SE, Dana WJ: Ifosfamide and mesna. Clin Pharm. 1990 Mar;9(3):179-91. [2107997 ]
  10. Dechant KL, Brogden RN, Pilkington T, Faulds D: Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs. 1991 Sep;42(3):428-67. [1720382 ]
  11. FDA label
  12. Drugs.com [Link]
  13. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated GenesNot Available

Targets

1. DNA
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Furlanut M, Franceschi L: Pharmacology of ifosfamide. Oncology. 2003;65 Suppl 2:2-6. [14586139 ]
  2. Hartley JM, Spanswick VJ, Gander M, Giacomini G, Whelan J, Souhami RL, Hartley JA: Measurement of DNA cross-linking in patients on ifosfamide therapy using the single cell gel electrophoresis (comet) assay. Clin Cancer Res. 1999 Mar;5(3):507-12. [10100700 ]
  3. Willits I, Price L, Parry A, Tilby MJ, Ford D, Cholerton S, Pearson AD, Boddy AV: Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer. Br J Cancer. 2005 May 9;92(9):1626-35. [15827549 ]
  4. Lokiec F: Ifosfamide: pharmacokinetic properties for central nervous system metastasis prevention. Ann Oncol. 2006 May;17 Suppl 4:iv33-6. [16702183 ]
General Function:
Zinc ion binding
Specific Function:
Methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance. Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Mediates transcriptional repression by direct binding to HDAC2. In association with DNMT3B and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9.
Gene Name:
DNMT1
Uniprot ID:
P26358
Molecular Weight:
183163.635 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
  3. Carter NJ, Keam SJ: Trabectedin : a review of its use in the management of soft tissue sarcoma and ovarian cancer. Drugs. 2007;67(15):2257-76. [17927287 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.
Gene Name:
NR1I2
Uniprot ID:
O75469
Molecular Weight:
49761.245 Da
References
  1. Harmsen S, Meijerman I, Beijnen JH, Schellens JH: Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor. Cancer Chemother Pharmacol. 2009 Jun;64(1):35-43. doi: 10.1007/s00280-008-0842-3. Epub 2008 Oct 7. [18839173 ]