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Temozolomide

Anticancer drugs Pharmacokinetics Toxicological effects The treatment of recurrent glioblastoma multiforme tumor Clinical evaluation Patent No Chemical Properties Uses Production methods
Temozolomide
Temozolomide structure
CAS No.
85622-93-1
Chemical Name:
Temozolomide
Synonyms
TZM;M&temodar;B 39831;mb39831;m&b39831;nsc362856;ccrg81045;8-Carbamoy;TeMozoMide
CBNumber:
CB2708199
Molecular Formula:
C6H6N6O2
Formula Weight:
194.15084
MOL File:
85622-93-1.mol

Temozolomide Properties

Melting point:
212°C dec.
storage temp. 
2-8°C
solubility 
DMSO: soluble10mg/mL, clear
form 
powder
color 
white to light brown
Merck 
14,9139
InChIKey
BPEGJWRSRHCHSN-UHFFFAOYSA-N
CAS DataBase Reference
85622-93-1(CAS DataBase Reference)
SAFETY
  • Risk and Safety Statements
  • Hazard and Precautionary Statements (GHS)
Hazard Codes  T,Xi
Risk Statements  45-46-60-61-22-36/37/38
Safety Statements  24/25-45-36/37-26-53-36
WGK Germany  3
RTECS  NJ5927050
HS Code  29339900
Symbol(GHS):
Signal word: Danger
Hazard statements:
Code Hazard statements Hazard class Category Signal word Pictogram P-Codes
H302 Harmful if swallowed Acute toxicity,oral Category 4 Warning P264, P270, P301+P312, P330, P501
H315 Causes skin irritation Skin corrosion/irritation Category 2 Warning P264, P280, P302+P352, P321,P332+P313, P362
H319 Causes serious eye irritation Serious eye damage/eye irritation Category 2A Warning P264, P280, P305+P351+P338,P337+P313P
H335 May cause respiratory irritation Specific target organ toxicity, single exposure;Respiratory tract irritation Category 3 Warning
H340 May cause genetic defects Germ cell mutagenicity Category 1A, 1B Danger
H350 May cause cancer Carcinogenicity Category 1A, 1B Danger
H360 May damage fertility or the unborn child Reproductive toxicity Category 1A, 1B Danger
Precautionary statements:
P201 Obtain special instructions before use.
P261 Avoid breathing dust/fume/gas/mist/vapours/spray.
P280 Wear protective gloves/protective clothing/eye protection/face protection.
P305+P351+P338 IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.
P308+P313 IF exposed or concerned: Get medical advice/attention.

Temozolomide price More Price(13)

Manufacturer Product number Product description CAS number Packaging Price Updated Buy
Sigma-Aldrich 34219 Temozolomide VETRANAL , analytical standard 85622-93-1 25mg $343 2018-11-13 Buy
Sigma-Aldrich 1643543 Temozolomide United States Pharmacopeia (USP) Reference Standard 85622-93-1 200mg $817 2018-11-13 Buy
TCI Chemical T2744 Temozolomide >98.0%(HPLC) 85622-93-1 500mg $65 2018-11-22 Buy
TCI Chemical T2744 Temozolomide >98.0%(HPLC) 85622-93-1 5g $326 2018-11-22 Buy
Cayman Chemical 14163 Temozolomide ≥98% 85622-93-1 10mg $39 2018-11-13 Buy

Temozolomide Chemical Properties,Uses,Production

Anticancer drugs

Temozolomide is the first effective orally-taken imidazole and tetrazine-class anticancer drug which belongs to the second generation of an alkylating agent with antitumor activity without liver metabolic activation after oral administration. It is characterized by easily penetration through the blood-brain barrier, good tolerance and being not superimposed with other drugs toxicity, and having synergistic effect with radiotherapy which is suitable for treating malignant glioma recurrence after conventional treatment such as glioblastoma multiforme tumors or degenerative astrocytoma. It is first-line drug for treatment of metastatic melanoma.
Temozolomide had been first synthesized by Cancer Research UK Group, and then be transferred to the Schering-Plough Company (United States) for development. The drug is different from the existing Antineoplastic drug. It has a novel chemical structure and belongs to a four-imidazole derivative. Temozolomide does not play a direct role. At physiological pH, it is first quickly converted into active compound MTIC [5-(3-methyl-triazene-1-) imidazole-4-carboxamide] via non-enzymatically way. People think that the cytotoxicity of MTIC is mainly due to its DNA alkylation (methylation) effect. Alkylation mainly occurs in the O6 and N7 position of guanine. Basic and clinical studies of temozolomide have confirmed that it is effective in treating some of the most common glioma cells. In 1999, it has been approved for enter into market in EU and the US wherein the permitted indication in United States is mainly for second-line treatment of glioblastoma multiforme and degenerative star gliomas and approved indications of EU is for treating developing or relapsing glioblastoma multiforme which has already been subject to conventional therapy. The efficacy of temozolomide on treating glioblastoma multiforme has received more recognition in Europe.

Pharmacokinetics

This medicine can be completely oral absorbed and has a nearly 100% availability. It can exhibit a broad spectrum of activity in murine tumor model systems and can penetrate through the human blood-brain barrier. The toxic effects of temozolomide cells originate from its role in strong methylation of DNA bases. Under alkaline conditions, temozolomide can quickly be broken for formation of active methyl diazonium ion. Since the brain has a higher basicity than the surrounding tissue, so that the activation of this drug can relatively concentrate and occur at the tumor site. It has a strong anti-tumor effect with certain selectivity with its side-effect profile being alleviated, small bone marrow toxicity and improved patient tolerance.

Toxicological effects

Genetic Toxicity: Temozolomide has in vitro mutagenesis effect on bacteria (Ames test), and can cause the collapse of mammalian cell chromosomes (human peripheral blood lymphocytes clear test).
Reproductive toxicity: There currently have been no reproductive toxicity performed for temozolomide, but the toxicity study of repeated medication test of rat and dog have shown that when the administered doses of 50mg/m2 and 125mg/m2, for rat and dog, respectively (calculated by body surface area, equivalent to approximately 1/4 and 5/8 of maximum recommended dosage, respectively), this product is toxic to animal testicles exhibited as syncytial cells (i.e. immature sperm) occurs and testicular atrophy.
Carcinogenicity: There have been no conventional carcinogenicity studies about temozolomide yet. Giving 125 mg/m2 of temozolomide to rats in a cycle of 5 consecutive days per 28 days to (according to calculation of body surface area, it is comparable to the maximum recommended daily amount for human) for three cycles can produce breast cancer for both male and female rats. According to calculation of 25, 50, 125mg/m2 (according to the calculation of body surface area, it is roughly equivalent to 1/8 to 1/2 of the maximum recommended dosage) after administration of 6 cycles, the animals in all the dose group got breast cancer: at high-dose group, fibrosarcoma occurs in the heart, eyes, seminal vesicles, salivary glands, abdomen, uterus and prostate tissue. It is also appeared in seminal vesicle cancer, heart, nerve sheath tumors, optic nerve cancer, and Bernhard's adenocarcinoma. Moreover, adenoid tumor also occurs in other visible tissues such as animal skin, lung, pituitary, and thyroid.

The treatment of recurrent glioblastoma multiforme tumor

The treatment of Temozolomide for recurrent glioblastoma multiforme trials have confirmed upon clinical assays to be safe and effective. A randomized controlled trial in phase II have showed that 225 cases of glioblastoma multiforme patients suffering the first reoccurrence of pleomorphic glioblastoma who have been treated by temozolomide or procarbazine (every 56 days once every 28 d, oral administration of 125~150 mg/m2 per day) for 6 months, respectively, the temozolomide group of patients have got no disease deterioration with survival and overall survival rate being 21% and 60%, respectively. This was significantly higher than that in procarbazine group (8% and 44%). The average survival time and overall survival time for patients in the temozolomide group with no disease progression was 2.9 and 7.3 months, respectively, which were significantly higher than that in procarbazine group that was 1.9 and 5.8 months, respectively. The Experimental have also evaluated the health-related quality of life in both the first 3 months and 6 months after the starting of the treatment, the results also have confirmed that temozolomide group had more patients with quality of life being improved or remaining stable.
The main side effect for temozolomide is transient and non-retention bone marrow suppression which is both predictable and easy to handle with a trials incidence of 24%. Temozolomide is also prone to cause moderate nausea and vomiting in patients, however these adverse reactions can be prevented with conventional antiemetic therapy. The efficacy of temozolomide for treating recurrent glioblastoma multiforme efficacy and its property of adverse reaction were significantly better than the existing standard drug procarbazine.

Clinical evaluation

Temozolomide is effective in treating newly diagnosed glioblastoma multiforme cell tumor. A small II trial results has shown that 33 cases of such patients who had been subject to temozolomide (200mg/m2) treatment where 17 patients had achieved complete or partial remission, and other four patients were in stable condition. The average time from the disease remission to disease progression for 17 patients was seven months, and was two months for the treatment of non-responders with their average survival time being 12 months and 6 months. But the effect of temozolomide in treating newly diagnosed degenerative astrocytomas remains unclear.
Temozolomide is of high efficacy on glioma cells, especially has a significant effect on the most common pleomorphic glioblastoma. No matter in tumor response rates, or in patient survival and tolerability it all has a good effect. More importantly, the quality of patients’ life is significantly better than the existing standard drug procarbazine, moving a big step toward the treatment of tumors using this kind of drug. The first-line position of Temozolomide in treatment of progressive metastatic melanoma has been affirmed in clinical assays. Applications for applying it widely in Europe and the United States are being conducted. A recent randomized controlled trial results in III phase have shown about the 305 cases of these patients who subjected to temozolomide (200 mg/m2) and dacarbazine (every 21 days once a 5d, 250 mg/m2 per day) treatment, temozolomide group of patients had a overall survival and treatment response rates of 7.9 months and 13.5%, respectively, which was better than that of 5.7 months and 12.1% as observed in dacarbazine group. Patients in Temozolomide group had a better tolerance than dacarbazine group with its life-qualify evaluation (reflected by reduced physiological function) also significantly better than dacarbazine group (the rate of decline was 18% and 42% after three months of treatment, respectively). Melanoma skin tumors are rare skin cancer, even though it accounts for only about 4% of all skin cancers, but the mortality rate accounted for about 79% of all skin cancer. The current standard drug for treating it is still dacarbazine. Temozolomide has exhibited high clinical efficacy towards glial cells and melanoma, and thus is worthy of attention.
The above information is edited by the Chemicalbook of Dai Xiongfeng.

Patent No

DE 3237255; US 5260921

Chemical Properties

It is crystallized from dichloromethane, m.p. 212 °C (decomposition). UV maximal absorption wavelength (95% ethanol): 327nm.

Uses

Antineoplastic agents. Spontaneous and rapid degradation and produce the active metabolite MTIC in vivo, yielding anti-tumor effect.

Production methods

Amino-4-carboxamido-imidazole is first subject to nitrite diazotization, and has reaction with methyl isocyanate in dichloromethane for cyclization to obtain ammonium temozolomide.

Description

Temozolomide was launched for the first time in the UK for the treatment of patients with glioblastoma multiforme showing recurrence or progression after standard therapy. It can be considered as a cyclic variant of highly reactive triazenes producing a cascade of ionic or radical antitumoral species. Temozolamide is a 3-methyl analog of mitozolomide and was shown to be converted to cytotoxic triazene MCTIC. It can be prepared in 2 steps from 5- aminoimidazole-4-carboxamide by diazotization then cyclization with methylisocyanate. Mechanistically, the depletion of O6-alkylguanine-DNA alkyltransferase (OGAT) in cells or tumors was shown to be correlated with the cytotoxicity of temozolomide which is a potent inhibitor of this enzyme involved in DNA repair activity.
Further approval applications for the treatment of other malignant gliomas such as relapsed anaplastic astrocytoma, advanced metastatic melanoma were submitted.

Chemical Properties

Off-White to Light-Pink Crystalline Solid

Originator

CRC Technology (UK)

Uses

An apoptosis inducer which causes arrest at the G2/M cell cycle checkpoint.

Uses

Imidazotetrazine alkylating agent. An antineoplastic.

Uses

inhibits cancer cells similar to paclitaxel effective against paclitaxel-resistant tumours

Definition

ChEBI: An imidazotetrazine that is 3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine which is substituted at positions 3, 4, and 8 by methyl, oxo, and carboxamide groups, respectively. A prodrug for MTIC (5-(3-methyltriaz-1-en-1-yl)-1H-i idazole-4-carboxamide, formed by spontaneous hydrolysis of temozolomide in the body), it is used as an oral alkylating agent for the treatment of newly diagnosed malignant glioblastoma multiforme (concomitantly with radiotherapy) and malignant melanoma.

brand name

Temodar (Schering);Temodal.

Biological Activity

DNA methylating, chemotherapeutic agent. Displays antitumor activity against a board spectrum of tumors, including leukemias, lymphomas and solid tumors (IC 50 = 5.0 μ M for cytotoxicity against mouse TLX5 lymphoma cells).

Temozolomide Preparation Products And Raw materials

Raw materials

Preparation Products


Temozolomide Suppliers

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Capot Chemical Co.,Ltd.
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View Lastest Price from Temozolomide manufacturers

Image Release date Product Price Min. Order Purity Supply Ability Manufacturer
2018-08-20 Temozolomide
85622-93-1
US $1.00 / KG 1G 98% 100KG career henan chemical co
2018-08-20 Temozolomide
85622-93-1
US $1.00 / KG 1KG 98-100% 1000kg career henan chemical co

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