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Record Information
Version2.0
Creation Date2014-09-11 05:14:45 UTC
Update Date2014-12-24 20:26:56 UTC
Accession NumberT3D4750
Identification
Common NameBusulfan
ClassSmall Molecule
DescriptionBusulfan is a bifunctional alkylating agent, having a selective immunosuppressive effect on bone marrow. It is not a structural analog of the nitrogen mustards. It has been used in the palliative treatment of chronic myeloid leukemia (myeloid leukemia, chronic), but although symptomatic relief is provided, no permanent remission is brought about. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), busulfan is listed as a known carcinogen.
Compound Type
  • Alkylating Agent
  • Antineoplastic Agent, Alkylating
  • Drug
  • Immunosuppressive Agent
  • Metabolite
  • Myeloablative Agonist
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
1,4-Bis(methanesulfonoxy)butane
1,4-Butanediol dimethanesulfonate
1,4-Dimesyloxybutane
1,4-Dimethanesulfonoxybutane
Bisulfex
Busilvex
Busulfano
Busulfanum
Busulfex
Busulphan
Busulphane
Butanedioldimethanesulfonate
Buzulfan
Leucosulfan
Mablin
Mielucin
Misulban
Mitostan
Myeloleukon
Myleran
Sulfabutin
Sulphabutin
Tetramethylene bis(methanesulfonate)
Tetramethylene Dimethane Sulfonate
Tetramethylenester Kyseliny Methansulfonove
Chemical FormulaC6H14O6S2
Average Molecular Mass246.302 g/mol
Monoisotopic Mass246.023 g/mol
CAS Registry Number55-98-1
IUPAC Name4-(methanesulfonyloxy)butyl methanesulfonate
Traditional Namebusulfan
SMILESCS(=O)(=O)OCCCCOS(C)(=O)=O
InChI IdentifierInChI=1S/C6H14O6S2/c1-13(7,8)11-5-3-4-6-12-14(2,9)10/h3-6H2,1-2H3
InChI KeyInChIKey=COVZYZSDYWQREU-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as organosulfonic acid esters. These are esters of sulfonic acid, which have the general structure RS(=O)2OR' (R,R' = organyl, not H).
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassOrganic sulfonic acids and derivatives
Sub ClassOrganosulfonic acids and derivatives
Direct ParentOrganosulfonic acid esters
Alternative Parents
Substituents
  • Organosulfonic acid ester
  • Sulfonic acid ester
  • Sulfonyl
  • Methanesulfonate
  • Organic oxygen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organooxygen compound
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic 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 Point106-107°C
Boiling PointNot Available
Solubility6.9E+004 mg/L
LogP-0.52
Predicted Properties
PropertyValueSource
Water Solubility5.16 g/LALOGPS
logP-0.9ALOGPS
logP-0.76ChemAxon
logS-1.7ALOGPS
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area86.74 ŲChemAxon
Rotatable Bond Count7ChemAxon
Refractivity49.57 m³·mol⁻¹ChemAxon
Polarizability23.64 ųChemAxon
Number of Rings0ChemAxon
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, Positivesplash10-0a6r-4910000000-e9ddf91161b812713ab4JSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot AvailableJSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-014i-1490000000-7895468c598e6a0480c8JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-014i-0390000000-19a6e15d2bf397b244b1JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-014i-0390000000-19a6e15d2bf397b244b1JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-014i-1490000000-7895468c598e6a0480c8JSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0002-0290000000-d4b566ed54a53c849786JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0udi-3910000000-3801100c88a8c43def33JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-004r-9500000000-3dec1d870a9203efd37fJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0002-3090000000-aa607731139624cbe5bcJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004i-9110000000-7405cd0ebfa01ce907a0JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-004i-9000000000-4e28fa66f6cebb7272ccJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0uka-9530000000-c112640ccc30da208327JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0a4j-9000000000-ed8101663b60977229ecJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4i-9000000000-4f0ac4d1c58f92828a43JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0002-0090000000-1d2d39d4577a3e5e71adJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-000j-2960000000-3752c572e539716a5e2eJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-002f-9100000000-644c96579ffd326045dcJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
Toxicity Profile
Route of ExposureCompletely absorbed from the gastrointestinal tract. Busulfan is a small, highly lipophilic molecule that crosses the blood-brain-barrier. The absolute bioavailability, if a single 2 mg IV bolus injection is given to adult patients, is 80% Њ± 20%. In children (1.5 - 6 years old), the absolute bioavailability was 68% Њ± 31%. When a single oral dose is given to patients, the area under the curve (AUC) was 130 ngдуўhr/mL. The peak plasma concentration when given orally is 30 ng/mL (after dose normalization to 2 mg). It takes 0.9 hours to reach peak plasma concentration after dose normalization to 4 mg.
Mechanism of ToxicityBusulfan is an alkylating agent that contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain. Once busulfan is hydrolyzed, the methanesulfonate groups are released and carbonium ions are produced. These carbonium ions alkylate DNA, which results in the interference of DNA replication and RNA transcription, ultimately leading to the disruption of nucleic acid function. Specifically, its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks. This occurs through an SN2 reaction in which the relatively nucleophilic guanine N7 attacks the carbon adjacent to the mesylate leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis.
MetabolismBusulfan is extensively metabolizes in the hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. GSTA1 is the primary GST isoform that facilitates the the metabolism of busulfan. Other GST isoforms that are also involved are GSTM1 and GSTP1. At least 12 metabolites have been identified among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity. Route of Elimination: Following administration of 14C- labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces. Less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. Elimination of busulfan is independent of renal function. Half Life: 2.6 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)1, carcinogenic to humans. (9)
Uses/SourcesFor use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia (FDA has designated busulfan as an orphan drug for this use). It is also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsSigns of overdose include allergic reaction, unusual bleeding or bruising, sudden weakness or unusual fatigue, persistent cough, congestion, or shortness of breath; flank, stomach or joint pain; pronounced nausea, vomiting, diarrhea, dizziness, confusion, or darkening of the skin, chills, fever, collapse, and loss of consciousness.
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01008
HMDB IDHMDB15143
PubChem Compound ID2478
ChEMBL IDCHEMBL820
ChemSpider ID2384
KEGG IDC06862
UniProt IDNot Available
OMIM ID
ChEBI ID28901
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkBusulfan
References
Synthesis Reference

Timmis, G.M.; U S . Patent 2,917,432; December 15, 1959; assigned to Burroughs Wellcome
& Co., Inc.

MSDSLink
General References
  1. Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA: Platelet-derived serotonin mediates liver regeneration. Science. 2006 Apr 7;312(5770):104-7. [16601191 ]
  2. Valdez BC, Andersson BS: Interstrand crosslink inducing agents in pretransplant conditioning therapy for hematologic malignancies. Environ Mol Mutagen. 2010 Jul;51(6):659-68. doi: 10.1002/em.20603. [20577993 ]
  3. Hall AG, Tilby MJ: Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Blood Rev. 1992 Sep;6(3):163-73. [1422285 ]
  4. Ciurea SO, Andersson BS: Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009 May;15(5):523-36. doi: 10.1016/j.bbmt.2008.12.489. Epub 2009 Feb 12. [19361744 ]
  5. McCune JS, Holmberg LA: Busulfan in hematopoietic stem cell transplant setting. Expert Opin Drug Metab Toxicol. 2009 Aug;5(8):957-69. doi: 10.1517/17425250903107764. [19611402 ]
  6. Krivoy N, Hoffer E, Lurie Y, Bentur Y, Rowe JM: Busulfan use in hematopoietic stem cell transplantation: pharmacology, dose adjustment, safety and efficacy in adults and children. Curr Drug Saf. 2008 Jan;3(1):60-6. [18690982 ]
  7. Nath CE, Shaw PJ: Busulphan in blood and marrow transplantation: dose, route, frequency and role of therapeutic drug monitoring. Curr Clin Pharmacol. 2007 Jan;2(1):75-91. [18690856 ]
  8. FDA label
  9. 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

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. 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. Morales-Ramirez P, Gonzalez-Beltran F: Different behavior of SCE-eliciting lesions induced by low and high doses of busulfan. Environ Mol Mutagen. 2007 Oct;48(8):706-14. [17896789 ]
  4. Valdez BC, Andersson BS: Interstrand crosslink inducing agents in pretransplant conditioning therapy for hematologic malignancies. Environ Mol Mutagen. 2010 Jul;51(6):659-68. doi: 10.1002/em.20603. [20577993 ]
  5. Hall AG, Tilby MJ: Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Blood Rev. 1992 Sep;6(3):163-73. [1422285 ]
  6. Ciurea SO, Andersson BS: Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009 May;15(5):523-36. doi: 10.1016/j.bbmt.2008.12.489. Epub 2009 Feb 12. [19361744 ]
  7. McCune JS, Holmberg LA: Busulfan in hematopoietic stem cell transplant setting. Expert Opin Drug Metab Toxicol. 2009 Aug;5(8):957-69. doi: 10.1517/17425250903107764. [19611402 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.
Gene Name:
ESR1
Uniprot ID:
P03372
Molecular Weight:
66215.45 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.102 uMACEA_T47D_80hr_PositiveACEA Biosciences
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]