4342-03-4 Usage
Antineoplastic drug
Dacarbazine is a new type of purine precursor-class anticancer drug. It can interfere with purine biosynthesis, while having the role of alkylating agents together. It has inhibitory effects on mice sarcoma-180, lung cancer-755, melanoma B16 and leukemia L-1210. It takes effects on the G2 phase of the cell cycle with its main impact on RNA and protein synthesis, followed by DNA. Its oral absorption is not complete with large individual differences. After single-time intravenous injection, it reaches peak within 30 min and disappear after 6h. During the 6 h, the drug excreted from urine account for 30% of the total administered dose. It can’t penetrate through the blood-brain barrier.
Clinical cases mainly apply the citrate salt form of dacarbazine that appears as a white crystalline powder. Its aqueous solution exhibits strong acidicity with the pH being 1.9 to 2.3. It is mainly used for the treatment of malignant melanoma with a better efficacy than hydroxyurea. When being used in combination with vinblastine and BCNU, its efficacy can be improved. It can also be applied to the treatment of squamous cell carcinoma and undifferentiated carcinoma, leiomyosarcoma, fibrosarcoma and so on. However, it is ineffective in treating digestive tract tumors.
Pharmacodynamics
Dacarbazine is the structural analog of the precursor of the purine biosynthesis (see Figure 1), but with its biological effect being similar to the alkylating agent and belongs to the cell cycle non-specific drugs. It has inhibitory effects on several kinds of animal tumors with its major effects on in the G2 phase of the cell cycle with the inhibitory effect being more significant than RNA and protein synthesis.
Figure 1 the structural formula of dacarbazine.
Pharmacokinetics
Because of the incomplete oral absorption and being volatile, dacarbazine can only be subject to the intravenous administration. It first becomes mono-methyl form in the liver through N-demethylation and then metabolized into aminoimidazole carboxamide (AIC) and diazomethane. The active carbon ions are formed from the diazomethane. Dacarbazine has biphasic plasma declining with the half-life being 19 minutes and 5 hours, respectively. It is quickly removed from the tubular secretion. Within 6 hours, about 40% of it is discharged in its prototype form with the primary metabolite in urine being AIC.
This information is edited by Xiongfeng Dai from lookchem
Clinical application
It has a better efficacy in treating the spread of malignant melanoma than other anti-cancer drugs. It is most commonly adopted of single-dose treatment and can also be used in combination with BCG, transfer factor and melphalan for immunochemical combination therapy. Applying (ABVD), (MOPP) with alternating method to some poor-outcome patients of advanced Hodgkin's disease can achieve long-term complete remission or even complete curing. It has certain efficacy in the treatment of various kinds of sarcomas, brain tumors, lung squamous cell carcinoma and small cell carcinoma, and children neuroblastoma.
Medicine interactions
1. When being used in combination with other drugs of bone marrow suppression, we should reduce the amount of this product.
2. When being used in combination with interleukin, the risk of allergic reactions will increase.
3. When applying this product to lively vaccines will increase the risk of infection caused by lively vaccines. Patients receiving immunosuppressive should not receive lively vaccines. Leukemia patient in remission period should at least stop three months before being subject to lively vaccines.
4. There is incompatibility when using dacarbazine in combination with hydrocortisone sodium succinate. Therefore, taking together is not suitable.
Side effects
Different sources of media describe the Side effects of 4342-03-4 differently. You can refer to the following data:
1. 1. Myelosuppression is often the major reason for limiting the dose with mainly affecting the white blood cells and platelets. The effect, compared with traditional mustard, occurs at relatively late time. Neutropenia often occurred in 10 days after treatment while thrombocytopenia occur in 10 to 15 days, but the last two can also be delayed to appear until after 2 to 4 weeks of the last treatment.
2. Nausea and vomiting often occur in 1 to 3 hours after administration with vomiting being sustainable to 12 hours. The side effects can occur in 90% of patients and can be very serious. Application of phenothiazines before medication may be invalid. Under rare circumstances, intractable nausea and vomiting make treatment must be stopped. Most patients can tolerate gradually, and these symptoms can be reduced within 1-2 days after the treatment.
3. It has been reported in patients subjected to dacarbazine of the emergence of a "flu-like" syndrome, including fever, muscle pain and fatigue. Other side effects include: injection site pain, facial flushing, abnormal feeling, hair loss and increased liver enzyme levels. There are also reports of liver necrosis. Dacarbazine is teratogenic and carcinogenic in animals. Allergies are relatively rare.
4. This drug can be put into FDA pregnancy category C.
2. Approximately 40% of the drug is excreted unchanged, but both the 5-aminoimidazole-4-carboxamide (AIC, formed through the action of CYP1A enzymes) and the carboxylic acid (AIC hydrolysis product) are major urinary metabolites. Leukopenia and thrombocytopenia are the most common side effects and may be fatal. Patients also are at risk for hepatotoxicity, including hepatocellular necrosis.
Precautions
1. it has mutagenic or teratogenic effects. There may be carcinogenic and pregnant women should be disabled.
2. during the administration, the patients should stop breast-feeding.
3. Interference of the diagnostic agent: when using this product, there may be transient increases in the level of blood urea nitrogen, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase.
4. Patients of varicella zoster should be disabled or should be prohibited for treatment of live virus vaccine.
5. Patients of renal dysfunction, infection should take with caution.
6. During the medication, the patients should be subject to monitoring of regular blood urea nitrogen, creatinine, uric acid, bilirubin, alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase.
Chemical Properties
Different sources of media describe the Chemical Properties of 4342-03-4 differently. You can refer to the following data:
1. It appears as slightly yellow crystalline powder with the M.p. being 205 ℃. It has also been reported of 250-255 ℃ (decomposition). It is easily soluble in acid, slightly soluble in methanol, ethanol but insoluble in water. It can be subject to decomposition when being exposed to heat, light and acid labile.
2. Off-white Cryst
3. Dacarbazine is a white to ivory-colored
crystalline solid.
Uses
Different sources of media describe the Uses of 4342-03-4 differently. You can refer to the following data:
1. It belongs to antineoplastic agent. It is clinically used for the treatment of malignant melanoma with being effective in about 20-30% cases. Combination with vincristine and BCNU can further improve the efficacy. In addition, it also has certain efficacy in treating lung squamous cell carcinoma, sarcoma, leiomyosarcoma and fibrosarcoma but with poor efficacy in treating gastrointestinal cancer.
2. Used as an antineoplastic. Used in the treatment of malignant melanoma and sarcomas.
3. progestogen
4. Dacarbazine is used as an antineoplastic for treatment of malignant melanoma and sarcomas.
Production method
Take ethyl cyanoacetate as raw material, go through addition, amination, diazotization, coupling, reduction, formylation, cyclization, and, diazotization, condensation, through intermediate β-imino-β-ethoxy propionate hydrochloride, α-acetamide hydrochloride, α-amidino-α-phenylazo acetamide hydrochloride, 5-amino-imidazole-4-carboxamide hydrochloride to obtain it.
Description
Dacarbazine is nevertheless considered the first representative of the series of triazene
derivatives. It has been shown that it is an alkylating agent, and thus this drug inhibits RNA
and protein synthesis to a greater degree than DNA. Dacarbazine is used intravenously for
Hodgkin’s disease, soft-tissue sarcoma, and metastatic melanoma. A synonym of this drug
is diticene.
Definition
ChEBI: A monocarboxylic acid amide that is 1H-imidazole-4-carboxamide which is substituted at position 5 by a 3,3-dimethyltriaz-1-en-1-yl group. It is used for the treatment of metastatic malignant melanoma, and in combination with other drugs
or the treatment of Hodgkin's disease and soft-tissue sarcoma.
Indications
Dacarbazine (DTIC-Dome) is activated by photodecomposition
and by enzymatic N-demethylation.
Eventual formation of a methyl carbonium ion results
in methylation of DNA and RNA and inhibition of nucleic
acid and protein synthesis. As with other alkylating
agents, cells in all phases of the cell cycle are susceptible
to dacarbazine.
The plasma half-life of dacarbazine is biphasic, with
a distribution phase of 19 minutes and an elimination
phase of 5 hours. The drug is not appreciably protein
bound, and it does not enter the central nervous system
(CNS). Urinary excretion of unchanged drug is by renal
tubular secretion. Dacarbazine metabolism and decomposition
is complex.
Dacarbazine is the most active agent used in metastatic
melanoma, producing a 20% remission rate. It is also
combined with doxorubicin and other agents in the treatment
of various sarcomas and Hodgkin’s disease.
Dacarbazine may cause severe nausea and vomiting.
Leukopenia and thrombocytopenia occur 2 weeks after
treatment, with recovery by 3 to 4 weeks. Less common
is a flulike syndrome of fever, myalgias, and malaise.
Alopecia and transient abnormalities in renal and hepatic
function also have been reported.
General Description
Different sources of media describe the General Description of 4342-03-4 differently. You can refer to the following data:
1. White to ivory microcrystals or off-white crystalline solid.
2. Dacarbazine is available in 100- and 200-mg vials for IVadministration in the treatment of Hodgkin’s disease, malignantmelanoma, carcinoid cancer, neuroblastoma, andsoft tissue sarcoma. Resistance to dacarbazine has been primarilyattributed to enhanced activity of AGAT. The volumeof distribution exceeds the amount of water in thebody suggesting the compound distributes into body tissuespossibly the liver. The agent is not highly protein bound(20%) and is metabolized in the liver by CYP to give MTICand 4-amino-5-imidazole-carboxamide (AIC).Thedemethylation reaction is mediated by isozymes CYP1A1/2and CYP2E1. Elimination occurs via the urine with 40% to50% occurring as unchanged drug. Dose-limiting myelosuppressionpresents as both leucopenia and thrombocytopenia.Other adverse effects include nausea, vomiting,flulike symptoms, photosensitivity, and pain at the injectionsite.
Air & Water Reactions
Insoluble in water.
Reactivity Profile
Dacarbazine decomposes explosively at its melting point (250°C). Decomposes in the presence of light. Sensitive to oxidation.
Fire Hazard
Flash point data for Dacarbazine are not available. Dacarbazine is probably combustible.
Biochem/physiol Actions
Dacarbazine is a purine analog of naturally occurring purine precursor 5-amino-1H-imidazole-4-carboxamide (AIC). It is a synthetic triazine antineoplastic agent that exerts cytotoxic effects by acting as an alkylating agent and by inhibiting DNA synthesis and inducing apoptosis. It is known to induce hepatotoxicity in mice. Dacarbazine is not cell cycle-phase specific.
Clinical Use
This DNA methylating agent is administered IV as a single agent in the treatment of malignant melanoma and in combination with other agents in the treatment of metastatic melanoma.
Safety Profile
Confirmed carcinogen
with experimental carcinogenic and
tumorigenic data. Poison by intraperitoneal
and parenteral routes. Moderately toxic by
ingestion and intravenous routes.
Experimental teratogenic effects. Human
systemic effects by intravenous route:
nausea or vomiting, leukopenia (reduced
white blood cell count), and changes in
dehydrogenase enzymatic activity. Mutation
data reported. When heated to
decomposition it emits toxic fumes of NOx.
Synthesis
Dacarbazine, 5-(3,3-dimethyl-1-triazeno)imidazol-4-carboxamide (30.6.5),
is made by diazotation of 5-aminoimidazol-4-carboxamide with nitrous acid, which results
in the formation of 5-diazoimidazol-4-carboxamide (30.6.4). Reacting this with dimethylamine gives the desired dacarbazine (30.6.5)
Potential Exposure
Dacarbazine is used in cancer chemo-
therapy. Dacarbazine is used as an antineoplastic agent in
the treatment of certain skin cancers, and is occasionally
used in the therapy of other neoplastic diseases which have
become resistant to alternative treatment.br Health professionals who handle this drug (for example,
pharmacists, nurses, and physicians) may possibly be
exposed during drug preparation, administration, or cleanup;
however, the risks can be avoided through use of appropriate
containment equipment and work practices
.People
receiving dacarbazine in treatment are also exposed.
Veterinary Drugs and Treatments
Dacarbazine has been used to treat relapsed canine lymphoma, soft
tissue sarcomas
and melanoma in dogs. In combination with doxorubicin,
dacarbazine has been evaluated to treat dogs with relapsed
lymphosarcoma. Ongoing studies evaluating various protocols are
ongoing for this indication.
Drug interactions
Potentially hazardous interactions with other drugs Aldesleukin: avoid concomitant use.Antipsychotics: avoid with clozapine, increased risk
of agranulocytosis.
Environmental Fate
The exact mechanism of action of dacarbazine is unknown;
however, several proposed mechanisms have been made
including inhibition of DNA synthesis by acting as a purine
analog, alkylating agent, and interference with sulfhydryl
groups. It is most commonly classified as an alkylating agent in
the triazene group. While the active compound of dacarbazine,
DTIC, is structurally similar to purines, its primary mechanism
of action precludes the agent from being classified as an antimetabolite.
Dacarbazine is a synthetic compound that is
metabolically activated to the active alkylating metabolite
methyl-triazeno-imidazole-carboxamide (MTIC) via the cytochrome
P450 system, primarily CYP1A1, CYP1A2, and CYP
2E1. MTIC is rapidly tautomerized into an inactive derivative,
5-aminoimidazole-4-carboxamide (AIC), which is renally
excreted. The entire process of activating DTIC occurs within
15 min of intravenous infusion. DTIC exerts its actions
throughout all phases of the cellular cycle. The antitumor
effects of this compound are related to the induction of methyl
adducts to DNA. The 70% of alkylation occurs at the N7
position of guanine. The cytotoxic and mutagenic effects of
MTIC are manifested through alkylation of DNA at the O6
guanine position, accounting for 6–8% of methylated bases
formed. This is primarily a result of generation of incorrect base
pairing, leading to DNA double strand breaks and apoptosis.
Metabolism
Dacarbazine (DTIC) is assumed to be inactive.
Dacarbazine is extensively metabolised in the liver
by the cytochrome P450 isoenzymes CYP1A2 and
CYP2E1 (and possibly in the tissues by CYP1A1)
to its active metabolite 5-(3-methyl-triazen-1-yl)-
imidazole-4-carboxamide (MTIC), which spontaneously
decomposes to the major metabolite 5-amino-imidazole-
4-carboxamide (AIC). About half of a dose is excreted in
the urine by tubular secretion; 50% as unchanged DTIC
and approximately 50% as AIC.
Shipping
UN3249 Medicine, solid, toxic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials.
Toxicity evaluation
Dacarbazine is a colorless to an ivory-colored crystalline solid
that must be reconstituted and administered as a parenteral
agent for intravenous injection. It is available as a dry powder in
100, 200, and 500mg vials that when reconstituted have
a standard concentration of 10 mg dacarbazine per 1 ml solution
and a pH of 3–4. Vials of dacarbazine should be refrigerated
(2–8°C) and protected from light. When exposed to light,
dacarbazine is rapidly decomposed to 4-diazoimidazole-5-carboxamide.
When exposed to high temperatures (250–255°C)
dacarbazine decomposes explosively. Dacarbazine is slightly
soluble in water. Dacarbazine may be diluted in either normal
saline or dextrose 5% water. Reconstituted solution is stable for
24 h at room temperature (20°C) and 96 h under refrigeration
(4°C); however, it is recommended by the manufacturer to
use the product within 8 and 72 h, respectively. Dacarbazine
should not be used if it turns pink, as this is a sign of
decomposition.
Incompatibilities
ncompatible with oxidizers (chlorates,
nitrates, peroxides, permanganates, perchlorates, chlorine,
bromine, fluorine, etc.); contact may cause fires or explo-
sions. Keep away from alkaline materials, strong bases,
strong acids, oxoacids, and epoxides. Explosive decom-
position reported @ 250℃
255℃
Waste Disposal
It is inappropriate and possi-
bly dangerous to the environment to dispose of expired or
waste drugs and pharmaceuticals by flushing them down
the toilet or discarding them to the trash. Household quanti-
ties 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 4342-03-4 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 4,3,4 and 2 respectively; the second part has 2 digits, 0 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 4342-03:
(6*4)+(5*3)+(4*4)+(3*2)+(2*0)+(1*3)=64
64 % 10 = 4
So 4342-03-4 is a valid CAS Registry Number.
InChI:InChI=1/C6H10N6O/c1-12(2)11-10-6-4(5(7)13)8-3-9-6/h3H,1-2H3,(H2,7,13)(H,8,9)/b11-10+
4342-03-4Relevant articles and documents
Optimized synthesis process of anticancer drug dacarbazine
-
Paragraph 0034; 0035, (2019/10/17)
The invention provides an optimized synthesis process of an anticancer drug dacarbazine. The optimized synthesis process of the anticancer drug dacarbazine comprises the following steps: synthesis ofglycine methyl ester, synthesis of N-formylglycine methyl ester, synthesis of alpha-methyl isocyanoacetate, synthesis of alpha-isocyanoacetamide, synthesis of 5-amino-4-imidazolecarboxamide and synthesis of dacarbazine. Synthesis of the glycine methyl ester comprises the following steps: weighing 7.5 g of glycine and adding the glycine into a 500 mL round-bottom flask, taking 200 mL of redistilledmethanol as a solvent and cooling with stirring in an ice bath for 15 min; weighing 22 mL of thionyl chloride by a syringe and slowly dropwise adding the thionyl chloride into the reaction flask to react overnight at room temperature; and removing excess thionyl chloride and methanol by rotary evaporation at the room temperature, dissolving the residues by using as little hot methanol as possible, quickly adding a large amount of cold diethyl ether, and cooling in the reaction bottle in an ice bath. By improving the synthesis process of the anticancer drug dacarbazine, the optimized synthesisprocess of the anticancer drug dacarbazine has the advantages of reasonable synthesis circuit, cheap raw materials, mild reaction conditions and high total yield, thereby effectively solving the problems and defects in the prior art.
THERAPEUTIC FOR HEPATIC CANCER
-
, (2011/02/18)
A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
Medicines for treating tumoral pathologies containing the ro5-4864 compound and an apoptosis-inducing agent
-
, (2008/06/13)
The invention concerns the use of Ro5-4864, and compounds derived therefrom, for preparing medicines for treating tumoral pathologies. The invention also concerns said compounds combined with an apoptosis-inducing agent, as combination products for simultaneous, separate or prolonged use, in cancer therapy.