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| Name | Busulfan | ||||||||||||||||||||||||||||||||||||
| Accession Number | DB01008 (APRD00664) | ||||||||||||||||||||||||||||||||||||
| Type | small molecule | ||||||||||||||||||||||||||||||||||||
| Groups | approved | ||||||||||||||||||||||||||||||||||||
| Description | An alkylating agent having a selective immunosuppressive effect on bone marrow. 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. [PubChem] |
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| Structure |
Download: MOL | SDF | SMILES | InChI Display: 2D Structure | 3D Structure |
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| Synonyms |
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| Brand name mixtures | Not Available | ||||||||||||||||||||||||||||||||||||
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| CAS number | 55-98-1 | ||||||||||||||||||||||||||||||||||||
| Weight |
Average: 246.302 Monoisotopic: 246.023179560 |
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| Chemical Formula | C6H14O6S2 | ||||||||||||||||||||||||||||||||||||
| InChI Key | InChIKey=COVZYZSDYWQREU-UHFFFAOYSA-N | ||||||||||||||||||||||||||||||||||||
| InChI |
InChI=1S/C6H14O6S2/c1-13(7,8)11-5-3-4-6-12-14(2,9)10/h3-6H2,1-2H3
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| IUPAC Name |
4-(methanesulfonyloxy)butyl methanesulfonate
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| SMILES |
CS(=O)(=O)OCCCCOS(C)(=O)=O
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| Mass Spec | Not Available | ||||||||||||||||||||||||||||||||||||
| Taxonomy | |||||||||||||||||||||||||||||||||||||
| Kingdom | Organic | ||||||||||||||||||||||||||||||||||||
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| Pharmacology | |||||||||||||||||||||||||||||||||||||
| Indication | For use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia (FDA has designated busulfan as an orphan drug for this use). Also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases. | ||||||||||||||||||||||||||||||||||||
| Pharmacodynamics | Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn leads to a miscoding of DNA. Alkylating agents are cell cycle-nonspecific and work by three different mechanisms, all of which achieve the same end result - disruption of DNA function and cell death. | ||||||||||||||||||||||||||||||||||||
| Mechanism of action | Busulfan 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. | ||||||||||||||||||||||||||||||||||||
| Absorption | Completely absorbed from the gastrointestinal tract. | ||||||||||||||||||||||||||||||||||||
| Volume of distribution | Not Available | ||||||||||||||||||||||||||||||||||||
| Protein binding | 32.4% | ||||||||||||||||||||||||||||||||||||
| Metabolism |
Mainly Hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. |
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| 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. | ||||||||||||||||||||||||||||||||||||
| Half life | 2.5 hours | ||||||||||||||||||||||||||||||||||||
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| Toxicity | Signs 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. | ||||||||||||||||||||||||||||||||||||
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| Pathways | Not Available | ||||||||||||||||||||||||||||||||||||
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| Properties | |||||||||||||||||||||||||||||||||||||
| State | solid | ||||||||||||||||||||||||||||||||||||
| Melting point | 287 oC | ||||||||||||||||||||||||||||||||||||
| Experimental Properties |
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| Synthesis Reference | Not Available | ||||||||||||||||||||||||||||||||||||
| General Reference |
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| External Links |
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| PDB Entries | Not Available | ||||||||||||||||||||||||||||||||||||
| FDA label | show (50.7 KB) | ||||||||||||||||||||||||||||||||||||
| MSDS | show (67.5 KB) | ||||||||||||||||||||||||||||||||||||
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| Drug Interactions | Not Available | ||||||||||||||||||||||||||||||||||||
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| Targets |
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1. DNA Pharmacological action: yesActions: cross-linking/alkylation DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes. Gene Sequence: FASTAReferences:
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| Enzymes |
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Actions: substrate
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. The enzyme also hydroxylates etoposide UniProt ID: P08684![]() Gene: CYP3A4 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
2. Glutathione S-transferase A2 Actions: substrateConjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles UniProt ID: P09210![]() Gene: GSTA2 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
3. Glutathione S-transferase A1 Actions: substrateConjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles UniProt ID: P08263![]() Gene: GSTA1 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
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This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.