Busulfan

Busulfan Basic information
Product Name:Busulfan
Synonyms:BUSULFAN;tetramethylene bis(methanesulfonate);1,4-dimethanesulfonoxybutane;1,4-Bis(methyl sulfonoxy)butane;1,4-Butanediol dimethyl sulfonate;(1,4-bis(methanesulfonyloxy)butane);1,4-bis(methanesulfonoxy)butane;1,4-Bis(methane-sulponyloxy)butane
CAS:55-98-1
MF:C6H14O6S2
MW:246.3
EINECS:200-250-2
Product Categories:Biochemistry;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;MYLERAN;Antitumors for Research and Experimental Use;55-98-1
Mol File:55-98-1.mol
Busulfan Structure
Busulfan Chemical Properties
Melting point 114-117 °C(lit.)
Boiling point 359.3°C (rough estimate)
density 1.305 (estimate)
refractive index 1.5630 (estimate)
Fp 9℃
storage temp. Inert atmosphere,Room Temperature
solubility Very slightly soluble in water, freely soluble in acetone and in acetonitrile, very slightly soluble in ethanol (96 per cent).
form Crystalline Powder
color Pale Brown
Water Solubility Decomposes
Merck 14,1505
BRN 1791786
Stability:Moisture Sensitive
CAS DataBase Reference55-98-1(CAS DataBase Reference)
IARC1 (Vol. 4, Sup 7, 100A) 2012
EPA Substance Registry SystemBusulfan (55-98-1)
Safety Information
Hazard Codes T+,T,F
Risk Statements 45-26/27/28-63-46-36/37/38-23/24/25-39/23/24/25-11
Safety Statements 53-36/37/39-45-28A-36/37-16-7
RIDADR UN 2811 6.1/PG 1
WGK Germany 3
RTECS EK1750000
HazardClass 6.1(b)
PackingGroup III
HS Code 29053990
Hazardous Substances Data55-98-1(Hazardous Substances Data)
ToxicityLD50 i.v. in rats: 1.8 mg/kg (Scherf)
MSDS Information
ProviderLanguage
ACROS English
SigmaAldrich English
Busulfan Usage And Synthesis
DescriptionChemically, busulfan is classified as an alkyl sulfonate. One or both of the methylsulfonate ester moieties can be displaced by the nucleophilic N7 of guanine, leading to monoalkylated and cross-linked DNA. The extent of alkyl sulfonate–mediated DNA interstrand cross-linking has been shown to vary with the length of the alkyl chain between sulfonate esters, with the tetramethylene-containing busulfan showing less interstrand cross-linking capability than hexamethylene, methylene, or octamethylene analogues. Intrastrand cross-linking also occurs, preferentially at 5′-GA-3′ but also at 5′-GG-3′ sequences. Alkylation of Cys sulfhydryl groups is yet another mechanism of cytotoxicity.
Chemical PropertiesWhite Crystalline Solid
OriginatorMyleran,Burroughs- Wellcome,US,1954
UsesAntineoplastic alkylating agent, the palliative treatment of chronic myeloid leukemia, and insect sterilant.
UsesAlkylating agent with antileukemic activity. Antineoplastic
UsesBusulfan USP (Myleran) is used to treat Chronic granulocytic leukemia; other myeloproliferative disorders.
DefinitionChEBI: A methanesulfonate ester that is butane-1,4-diol in which the hydrogens of the hydroxy groups are replaced by methanesulfonyl groups. An alkylating antineoplastic agent, it is used for the treatment of chronic myeloid leukemia (although it has been largely replaced by newer drugs). It is also used as an insect sterilant.
IndicationsBusulfan (Myleran) is a bifunctional methanesulfonic ester that forms intrastrand cross-linkages with DNA. The drug is well absorbed after oral administration and has a plasma half-life of less than 5 minutes. Metabolites and degradation products are excreted primarily in the urine.
Busulfan is used in the palliative treatment of chronic granulocytic leukemia. Daily oral therapy results in decreased peripheral white blood cells and improved symptoms in almost all patients during the chronic phase of the disease. Excessive uric acid production from rapid tumor cell lysis should be prevented by coadministration of allopurinol.
At usual therapeutic dosages, busulfan is selectively toxic to granulocyte precursors rather than lymphocytes. Thrombocytopenia and anemia and less commonly, nausea, alopecia, mucositis, and sterility also may occur. Unusual side effects of busulfan include gynecomastia, a general increase in skin pigmentation, and interstitial pulmonary fibrosis.

Manufacturing Process3.6 grams of redistilled 1,4-butanediol were dissolved in 10 ml of pyridine and the solution was cooled in ice and water. 9.6 grams of redistilled methanesulfonyl- chloride were added dropwise at such a rate that the temperature did not rise above 20°C. The solution was then allowed to stand at room temperature to; 30 minutes, during which time the temperature rose to 60°C. A thick precipitate of pyridine hydrochloride was formed.
The mass was cooled in ice water and was treated with 30 ml of ice cold water. On agitation, a white crystalline precipitate was formed. This was filtered off and washed well with ice cold water and allowed to drain on the pump. It weighed 7.8 grams and had a melting point of 100°C. 3.5 grams of the material were recrystallized from acetone and ether to give small white needles, having a melting point of 106°-107°C, unchanged by further recrystallization.
Brand nameMyleran (GlaxoSmithKline).
Therapeutic FunctionAntineoplastic
General DescriptionBusulfan is available as 2-mg tablets for oral administrationand 10-mL vials for IV administration in the treatment ofchronic myelogenous leukemia (CML) and in high-dosetherapy for refractory leukemia with bone marrow transplant.The agent is well absorbed when given orally, well distributedinto tissues, and crosses the blood-brain barrier.Metabolism occurs in the liver to give mainly methane sulfonic acid by the action of glutathione-S-transferase. Other identified metabolites in humanshave included tetrahydrothiophene-1-oxide, sulfalene,primarily in the urine, and the terminal elimination half-lifeis 2.5 hours. Adverse effects include dose-limiting myelosuppression;nausea and vomiting that occur commonly butare generally mild; and pulmonary symptoms including interstitialpulmonary fibrosis, which is referred to as “busulfanlung,” occurs belatedly (1–10 years posttreatment) andalthough rare, it is severe. Other adverse effects includemucositis, skin rash, impotence, amenorrhea, infertility, hepatoxicity,insomnia, anxiety, and an increased risk of secondarymalignancies. At normal doses, the agent is welltolerated except for the myelosuppression that occurs. Thishas allowed for high-dose therapy with the agent when accompaniedby bone marrow transplant to counter the myelosuppressiveeffects.
General DescriptionWhite crystals or powder.
General DescriptionAs an alternative to utilizing aziridines as electrophilic species,it was found that simply utilizing a carbon chain terminated atboth ends by leaving groups gave compounds capable of actingas cross-linking agents.Busulfan utilizestwo sulfonate functionalities as leaving groups separated by afour-carbon chain that reacts with DNA to primarily form intrastrandcross-link at 5'-GA-3' sequences.The sulfonatesare also subject to displacement by the sulfhydryl functionsfound in cysteine and glutathione, and metabolic products areformed as a result of nucleophilic attack by these groups togenerate sulfonium species along with methane sulfonicacid.This is followed by conversion to tetrahydrothiophene,and further oxidation products are subsequently produced togive the sulfoxide and sulfone. The cyclic sulfone known assulfolane may be further oxidized to give 3-hydroxysulfolane.
Air & Water ReactionsBusulfan is an alkylating agent which hydrolyzes in water. .
Reactivity ProfileBusulfan is an alkylating agent which hydrolyzes in water. . Strong reducers may yield hydrogen sulfide.
HazardExtremely toxic, carcinogen, clastogenic, teratogenic, immunosuppressive, delayed bone marrow aplasia, cataracts, pigmentation, pulmonary thrombosis, cardiotoxic effects, thrombocytopenia.
Fire HazardFlash point data for Busulfan are not available. Busulfan is probably combustible.
Clinical UseBusulfan is used in the treatment of chronic myelogenous leukemia and can be administered either orally or by IV infusion.
Side effectsSerious bone marrow hypoplasia and myelosuppression are possible with this agent, and recovery from busulfaninduced pancytopenia can take up to 2 years.
Safety ProfileConfirmed carcinogen producing leukemia, kidney, and uterine tumors. Experimental neoplastigenic and tumorigenic data. Poison by ingestion, subcutaneous, intraperitoneal, intravenous, and possibly other routes. Ingestion by pregnant women can cause cancer of the reproductive system of the fetus includtng the uterus. Human teratogenic effects by ingestion and possibly other routes include developmental abnormaltties of the eye, ear, craniofacial area including the nose and tongue, gastrointestinal system, endocrine system, urogenital system, and other unspecified areas. Other human reproductive effects by ingestion and possibly other routes include: impotence, changes in the uterus, cervix, and vagina, and menstrual-cycle dtsorders. Experimental reproductive effects. Human systemic effects by ingestion: general arteriolar or venous ddation of the eye, changes in structure or function of salivary glands. When heated to decomposition it emits toxic fumes of SOx. See also SULFONATES.
SynthesisBusulfan, 1,4-butandioldimethansulfonate (30.2.3.1), is made by reacting butandiol with methanesulfonyl chloride.

Synthesis_55-98-1

Veterinary Drugs and TreatmentsBusulfan may be useful in the adjunctive therapy of chronic granulocytic leukemias or polycythemia vera in small animals. Not commonly used in veterinary medicine.
Drug interactionsPotentially hazardous interactions with other drugs
Antibacterials: concentration increased by metronidazole.
Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.
Antifungals: metabolism inhibited by itraconazole, monitor for signs of busulfan toxicity.


Carcinogenicity1,4-Butanediol dimethanesulfonate is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.
MetabolismBusulfan is extensively metabolised in the liver, mainly by conjugation with glutathione, either spontaneously or mediated by the enzyme glutathione-S-transferase. About 12 inactive metabolites have been identified, which are excreted in the urine. About 1% of busulfan is excreted unchanged. Elimination in the faeces is considered to be negligible.
references[1]. probin v, wang y, zhou d. busulfan-induced senescence is dependent on ros production upstream of the mapk pathway. free radic biol med, 2007, 42(12): 1858-1865.
[2]. probin v, wang y, bai a, et al. busulfan selectively induces cellular senescence but not apoptosis in wi38 fibroblasts via a p53-independent but extracellular signal-regulated kinase-p38 mitogen-activated protein kinase-dependent mechanism. j pharmacol exp ther, 2006, 319(2): 551-560.
[3]. choi yj, ok dw, kwon dn, et al. murine male germ cell apoptosis induced by busulfan treatment correlates with loss of c-kit-expression in a fas/fasl- and p53-independent manner. febs lett, 2004, 575(1-3): 41-51.
Busulfan Preparation Products And Raw materials
Raw materialsMethanesulfonyl chloride-->1,4-Butanediol
(+)-1,4-DI-O-TOSYL-2,3-O-ISOPROPYLIDENE-D-THREITOL (R)-1,4-DITOSYLOXY-2-BUTANOL (-)-1,4-DI-O-TOSYL-2,3-O-ISOPROPYLIDENETHREITOL (+)-1,4-DI-O-MESYL-2,3-O-ISOPROPYLIDENETHREITOL AURORA KA-611 AKOS BBS-00002040 dimethylmyleran (R)-1,2,4-BUTANETRIOL TRIMESYLATE SALOR-INT L163503-1EA (S)-1,2,4-BUTANETRIOL TRIMESYLATE CYCLOBUTANE (S)-1,2,4-TRITOSYL BUTANETRIOL AKOS 90005 1,2,4-TRIS(METHANESULFONYLOXY)BUTANE AURORA KA-659 1,4-BUTANEDIOL BIS(2,2,2-TRIFLUOROETHANE SULPHONATE) methanesulfonate (+)-1 4-DI-O-TOSYL-D-THREITOL

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