154-93-8 Usage
Description
Carmustine, also known as Bischloroethyl nitrosourea (BCNU), is a nitrogen mustard β-chloro-nitrosourea compound derived from mustard gas. It is an alkylating agent that forms interstrand crosslinks in DNA, preventing DNA replication and transcription, leading to apoptosis. Carmustine is a slightly yellow crystalline powder with a melting point of 30-32°C and is soluble in methanol, ethanol, and water. It is categorized as a toxic substance and is available under the brand names Bicnu and Gliadel.
Uses
Used in Anticancer Applications:
Carmustine is used as an anticancer drug for the treatment of various types of cancer, including acute leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, primary or metastatic brain tumors, malignant melanoma, breast cancer, lung cancer, gastrointestinal cancer, Ewing's sarcoma, and Burkitt's lymphoma. It is also used topically to treat mycosis fungoides. Carmustine may be used alone or in combination with other antineoplastic agents to enhance chemo-sensitivity and efficacy in resistant cases.
Used in Drug Delivery Systems:
Carmustine is used in the development of novel drug delivery systems to overcome its limitations and enhance its applications and efficacy against cancer cells. Various organic and metallic nanoparticles have been employed as carriers for Carmustine delivery, aiming to improve its delivery, bioavailability, and therapeutic outcomes.
Used in Surgical Adjuncts:
Carmustine is used as an intracavity surgical adjunct for recurrent glioblastoma multiforme and high-grade malignant glioma, in the form of a BCNU-impregnated polymer wafer. These wafers were approved by the US Food and Drug Administration (FDA) in 1996 and reapproved in 2003.
Used as an Alkylating Agent:
Carmustine is used as an alkylating agent that interacts with DNA, RNA, and proteins, causing DNA interstrand cross-linking, which is cytotoxic and leads to apoptotic cell death. It is also reported to inhibit glutathione reductase, thioredoxin reductase, and lipoamide dehydrogenase.
Used in Clinical Trials:
Carmustine has been tested in clinical trials as a cytostatic agent for Hodgkin's and non-Hodgkin's lymphoma, myeloma, malignant melanoma, glioblastoma, and other brain tumors.
Used in IV Administration:
Carmustine is available in a 100-mg vial for intravenous (IV) administration in the treatment of several types of brain tumors, Hodgkin's and non-Hodgkin's disease, and multiple myeloma. The agent is very lipid-soluble and easily crosses the blood-brain barrier, achieving concentrations greater than 50% of those seen in plasma.
Used in Implantable Wafers:
Carmustine is also available as an implantable wafer containing 7.7 mg of the drug for intracavity implantation in the treatment of glioblastoma multiforme.
Cyclically non-specific anti-tumor drug
It appears as colorless or yellowish or yellowish green crystal or crystalline powder and is odorless. It is insoluble in water and soluble in methanol or ethanol. Its hydrous solution is stable at pH4 but will be subject to rapid decomposition at solution of pH above 7.
Carmustin, together with lomustine, fotemustine and semustine are currently the most widely used cyclically non-specific anti-tumor drugs. It belongs to nitrosourea alkylating agent, although with the role of alkylating agents, has no cross-resistance with general alkylating agent. It is characterized by high lipid solubility, broad anti-tumor spectrum the alkylating agent is generally no cross-resistance with high fat-soluble, broad spectrum anti-tumor, quick onset and easily penetrating through the blood-brain barrier and so on. In the body, it can be decomposed into two active ingredients with one having carbamoyl activity and the other being as alkylating agent that can react with the DNA polymerase to inhibit the synthesis of RNA and DNA. It has effect on the proliferation of cells in each stage while being insensitive to non-proliferating cells. It is easily absorbed orally. It enters the brain at one hour after the intravenous administration. At six hours after administration, the brain drug concentration can reach about 60% to 70% of the plasma concentration with in vivo distribution being the highest in the liver, bile, kidney and spleen. This product has a short half-life being less than 15 minutes. But its metabolites have long half-life, and still have anti-cancer effects with being slowly released after binding to the plasma protein. Therefore, its effect can last long and produce delayed toxicity. This product is rapidly metabolized in the blood after being absorbed with the metabolites excreted slowly and the plasma concentration still remaining high after 48 ??hours. 60% is excreted through urine in the form of metabolites.
It is commonly used in the treatment of primary and secondary brain cancer, Hodgkin's disease, meningeal leukemia. It can also be applied for the treatment of multiple myeloma, lymphoma, breast cancer, lymphoma, melanoma, lung cancer; combination with fluorouracil can be adopted for treating colorectal cancer and gastric cancer; it can be used for treating bronchus lung cancer when being used in combination with methotrexate and cyclophosphamide. Carmustin is also effective in treating cancer of head portion as well as testicular cancer.
Toxic reaction
1, bone marrow suppression: it is dose-limiting toxicity, exhibiting as severe neutropenia and thrombocytopenia, usually occurs at 3 to 5 weeks after administration and will last for 1 to 3 weeks with the lowest suppression point occurring in 3 to 5 weeks with the ease being slowly than other alkylating agents.
2, gastrointestinal reactions: severe nausea, vomiting usually begins two hours after administration and will last for 4 to 6 hours. Administration of antiemetic agent before the treatment can prevent this.
3 Other reactions: burning sensation can immediately happen at injection site and limbs. Rare toxicity including liver and kidney dysfunction, usually occur upon large doses administration. It has been reported of the occurrence of painless jaundice and hepatic coma as well as pulmonary fibrosis.
Carmustin
Carmustin belongs to nitrosourea alkylating agents. On the one hand, it binds to DNA through alkylation. On the other hand, it acts on the protein through carbamoylation. It can inhibit DNA polymerase, thus preventing DNA and RNA synthesis with the strongest effect on the G1-s transition period as well as blocking effect on the s-phase, and further enhanced effect on the G2 phase and also certain effect on the G0 phase. It is a cell-cycle non-specific drug. This product high an excellent lipid-solubility, low dissociation and can penetrate through the blood-brain barrier with its metabolites still having anti-cancer effects. It undergoes slow release after binding to protein, thus having a long-lasting efficacy. It has broad anti-tumor spectrum with excellent efficacy in the treatment of meningeal leukemia, brain and spinal cord metastasis of malignant tumors, Hodgkin's disease as well as acute leukemia. It also has certain efficacy on the treatment of breast cancer, lung cancer, bone metastasis, lymphatic sarcoma, melanoma and testicular cancer. It is effective for treating primary and secondary brain tumors. Topical administration has excellent efficacy in treating lymphoma papules. The drug, in combination with fluorouracil, vincristine, dacarbazine, consists FIVB protocol for the treatment of colon; together with fluorouracil and doxorubicin, it form FAB protocol for treating gastric cancer; in combination with vincristine and dacarbazine, it can be used for the treatment of melanoma; in combination with androgen, it can be used for the therapy of breast cancer.
The above information is edited by the lookchem of Dai Xiongfeng.
Production method
The product has three synthetic routes: 1. take ethylene imine as raw material, go through phosgene condensation to generate bis-(β-chloroethyl) urea, and then generate carmustin via nitrosation; 2.take urea as raw material, go through condensation, ring-opening, chlorination, nitrosation to obtain it; 3.take ethanolamine as raw materials, and generate carmustin through similar processes as methods2. The first method can generate the finished product with just two steps but with its raw material, phosgene and ethyleneimine, both being extremely toxic chemicals, therefore demanding a high-level labor protection and production equipment. The second method has readily available raw materials as well as convenient operation.
Toxicity grading
Highly toxic
Acute toxicity
Oral-rat LD50: 20 mg/kg; Oral-Mouse LD50: 19 mg/kg.
Hazardous characteristics of explosive
It may cause deadly harm to the human respiratory system and can cause pulmonary fibrosis, dyspnea and verticillium.
Flammability and hazard characteristics
Combustion can produce toxic nitrogen oxides, chlorides fumes; it can lead to poisoning: nausea, vomiting, leukopenia and thrombocytopenia as well as bone marrow damage.
Storage characteristics
Treasury: ventilation, low-temperature and dry; store it separately from food raw materials.
Extinguishing agent
Dry powder, foam, sand, carbon dioxide, water mist.
Originator
BCNU,Gencorp Aerojet,US
Manufacturing Process
A solution of sodium nitrite (6.9 g, 0.10 mole) in water (60 ml) was added
dropwise to a cold (0-5°C), stirred solution of 1,3-bis(2-chloroethyl)urea (8.0
g, 0.044 mole) in formic acid (50 ml). The reaction mixture was stirred further
at 0°C until the pale yellow oil that had formed solidified. The nitrosourea was
collected and washed quickly with cold water (2 x 10 ml), and dried in
vacuum; yield 6.7 g. (71%).
Therapeutic Function
Antitumor
Air & Water Reactions
Insoluble in water.
Reactivity Profile
Carmustin decomposes rapidly in acid and in solutions above pH 7; most stable in petroleum ether or aqueous solution at pH 4.
Hazard
Extremely toxic, central nervous system
depression, pulmonary fibrosis, renal and hepatic
damage, cytotoxic, immunosuppressive, carcino-
gen.
Fire Hazard
Flash point data for Carmustin are not available. Carmustin is probably combustible.
Biochem/physiol Actions
Carmustine is a DNA alkylating agent causing DNA interstrand crosslinks. Effective against glioma and other solid tumors.
Clinical Use
Alkylating agent:
Myeloma, lymphoma and brain tumours
Safety Profile
Confirmed carcinogen withexperimental carcinogenic and tumorigenic data. A humanpoison by parenteral route. An experimental poison byingestion, intravenous, intraperitoneal, parenteral, andsubcutaneous routes. Human systemic effects byparenteral, int
Synthesis
Carmustin, 1,3-bis-(2-chloroethyl)-1-nitrosourea (30.2.4.4), is made by
nitrating 1,3-bis(2-chloroethyl)urea with nitrogen trioxide.
Potential Exposure
BCNU has been used since 1971 as an
antineoplastic agent in the treatment of Hodgkin’slymphoma; multiple meyloma; and primary or metastatic
brain tumors. It also has been reported to have antiviral,
antibacterial, and antifungal activity, but no evidence was
found that it is used in these ways. BCNU is not known to
be naturally occurring. Health professionals who handle
this drug (for example, pharmacists, nurses, and physicians)
may possibly be exposed to BCNU during drug preparation, administration, or cleanup; however, the risks can be
avoided through use of containment equipment and proper
work practices
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine (increased risk
of agranulocytosis).
Carcinogenicity
Bis(chloroethyl) nitrosourea (BCNU) is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.
Environmental Fate
It is generally assumed that BCNU exerts its cytotoxicity
through the liberation of alkylating and carbamoylating
moieties. An alkylating entity, particularly chloroethyl carbonium
ion, is strongly electrophilic and can alkylate a variety
of biomolecules, including the purine and pyrimidine bases of
DNA. BCNU causes DNA interstrand cross-linking, which is
associated with cytotoxicity. The carbamoylation of lysine
residues of protein can inactivate certain enzymes, thus interfering
with DNA and RNA synthesis and repair processes. The
inhibition of glutathione reductase by this carbamoylation
further contributes to cytotoxicity.
Metabolism
Intravenous carmustine is rapidly metabolised, and no
intact drug is detectable after 15 minutes. It is partially
metabolised to active metabolites by liver microsomal
enzymes, which have a long half-life. It is thought that the
antineoplastic activity may be due to metabolites.
Approximately 30% of a dose is excreted in the urine after
24 hours, and 60-70% of the total dose after 96 hours.
About 10% is excreted as respiratory CO2
. Terminal halflife of the metabolites is about 1 hour.
Shipping
UN3249 Medicine, solid, toxic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials. UN2811 Toxic
solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-
Poisonous materials, Technical Name Required.
Toxicity evaluation
There is no information available on the environmental fate of
BCNU. However, it is predicted that BCNU spontaneously decomposes due to its high reactivity. Estimates indicate that
the half-life of BCNU particulates and vapor in air is 4.4 days.
Though expected to be highly mobile when adsorbed to soil
and suspended solids, it is likely that this adsorption may be
precluded by hydrolysis. Volatilization from soil or water is not
expected, and the potential for bioaccumulation is low. BCNU
degrades into 2-chloroethylamine, which is not considered
hazardous to the environment.
Incompatibilities
Acids and acid solutions above pH 7
cause rapid decomposition. Most stable at pH 4 in aqueous
solution or petroleum ether.
Waste Disposal
It is inappropriate and possibly dangerous to the environment to dispose of expired or
waste pharmaceuticals by flushing them down the toilet or
discarding them to the trash. Household quantities of
expired or waste pharmaceuticals may be mixed with wet
cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If
possible return the pharmaceutical to the manufacturer for
proper disposal being careful to properly label and securely
package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a
state licensed medical waste contractor to dispose by burial
in a licensed hazardous or toxic waste landfill or
incinerator.
Check Digit Verification of cas no
The CAS Registry Mumber 154-93-8 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 1,5 and 4 respectively; the second part has 2 digits, 9 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 154-93:
(5*1)+(4*5)+(3*4)+(2*9)+(1*3)=58
58 % 10 = 8
So 154-93-8 is a valid CAS Registry Number.
InChI:InChI=1/C5H9Cl2N3O2/c6-1-3-8-5(11)10(9-12)4-2-7/h1-4H2,(H,8,11)
154-93-8Relevant articles and documents
Method for preparing high-purity carmustine
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Paragraph 0062-0063; 0066-0082, (2020/04/17)
The invention provides a method for preparing high-purity carmustine. Specifically, the preparation method comprises a step of recrystallizing a crude carmustine product with an organic solvent, wherein the organic solvent is a mixed solvent of an alcohol solvent and water, and the alcohol solvent is preferably at least one selected from the group consisting of methanol, ethanol and isopropanol. The method can be used for preparing high-purity carmustine.
AN IMPROVED PROCESS FOR THE PREPARATION OF 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA
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Page/Page column 10; 11, (2017/09/27)
The present invention relates to an improved process for the preparation of 1,3-bis(2-chloroethyl)-1 -nitrosourea compound of formual-1 which is represented by the following structural formula:
Concatamers for Immunemodulation
-
, (2012/04/23)
The invention relates to a polymeric, non-coding nucleic acid molecule for modulation of the activity of the human and animal immune system as well as a method for the manufacture thereof and a vaccine, comprising the polymeric, non-coding nucleic acid molecule, wherein polymeric, non-coding nucleic acid molecules may be understood as non-coding nucleic acid molecules, comprising at least four covalently bound molecules (tetramer) or are assemblies of more non-coding nucleic acid molecules (high molecular polymers) which are covalently bound to each other.
