Temozolomide
TMZ · Temozolamide · temodar · TeMozoloMid · TZM · TeMozoMide · methazolastone · M&B 39831
Identifikatoren & physikalische Daten
| CAS No. | 85622-93-1 |
|---|---|
| Summenformel | C6H6N6O2 |
| Durchschnittliche Molmasse | 194,15 g/mol |
| Monoisotopische Masse | 194,05522343 g/mol |
| SMILES | Cn1nnc2c(C(N)=O)ncn2c1=O |
| InChIKey | BPEGJWRSRHCHSN-UHFFFAOYSA-N |
| PubChem CID | 5394 |
| ChEMBL | CHEMBL810 |
| ChEBI | CHEBI:72564 |
| EC No. | 630-358-9 |
| DTXSID | DTXSID5043714 |
Chemische & physikalische Eigenschaften
| XLogP | -1,1 |
|---|---|
| Polarare Oberfläche (TPSA) | 106 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 5 |
| Frei drehbare Bindungen | 1 |
| Schwere Atome | 14 |
| Formalladung | 0 |
| Komplexität | 315 |
| Arzneimittel | PharmaceuticalsPharmaceuticals -> Listed in ZINC15 |
| SpringerMaterials Properties | 15N nuclear magnetic resonance spectrum |
| LogP (Verteilungskoeffizient) | -2.8-1.08 |
| Löslichkeit | 5.09e+00 g/LDMSO: soluble10mg/mL, clear |
| Human Drugs | Breast FeedingLactationAntineoplastic AgentsAntineoplastic Agents, AlkylatingFDA approved drugs -> Active ingredientEMA approved medicines: Human medicine |
| Schmelzpunkt | 212 °C212°C dec. |
| Physical Description | Solid |
| Siedepunkt | 526.6±42.0 °C(Predicted) |
| Dichte | 1.97±0.1 g/cm3(Predicted) |
| Lagerbedingungen | 2-8°C |
| pKa (Säurekonstante) | 14.77±0.20(Predicted) |
| Aggregatzustand | powder |
| Farbe | white to light brown |
| Merck | 14,9139 |
| Stabilität | Stable for 2 years as supplied. Solutions in DMSO may be stored at -20° for up to 3 months. |
| Hauptanwendungen | forensics and toxicologypharmaceutical (small molecule)veterinary |
| InChI | InChI=1S/C6H6N6O2/c1-11-6(14)12-2-8-3(4(7)13)5(12)9-10-11/h2H,1H3,(H2,7,13) |
| InChIKey | BPEGJWRSRHCHSN-UHFFFAOYSA-N |
| SMILES | N1(C)C(=O)N2C=NC(C(N)=O)=C2N=N1 |
| CAS Datenbank | 85622-93-1(CAS DataBase Reference) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH204 (17.3%): Fire or projection hazard [Warning Explosives]P203, P210, P230, P234, P236, P240, P250, P260, P261, P264, P264+P265, P270, P271, P280, P301+P316, P301+P317, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P370+P380+P375, P401, P403+P233, P405, P501, and P503 (click each P-code to see the statement)Aggregated GHS information provided per 162 reports by companies from 19 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies. |
|---|---|
| Hazard Classes and Categories | Expl. 1.4 (17.3%) |
| Hepatotoxicity | Serum aminotransferase elevations occur during temozolomide therapy in up to 12% of patients, but these elevations are usually mild and self-limited, not requiring dose adjustment or drug discontinuation. An instance of serum aminotransferase elevation with jaundice was reported in the registration trials of temozolomide and subsequent to its approval. More strikingly, multiple single case reports and several case series of temozolomide hepatotoxicity have been reported in the literature. The onset of injury was typically within 2 to 8 weeks of starting temozolomide but several patients had received multiple courses before the onset of liver injury. The pattern of serum enzyme elevations was usually mixed initially, but the disease tended to be cholestatic. In several instances, jaundice was deep and prolonged. Features of hypersensitivity (rash, fever, eosinophilia) and autoantibody formation were not present. Liver histology demonstrated cholestasis and bile duct injury and a striking decrease in bile ducts (bile duct loss or paucity). Jaundice and pruritus tended to be prolonged and some patients developed vanishing bile duct syndrome, while others recovered clinically but had persistent serum alkaline phosphatase elevations during follow up and to the time of death from the brain tumor. Rechallenge was not done, but several patients subsequently received other antineoplastic agents, some of which were alkylating agents without recurrence of liver injury. |
| Drug Induced Liver Injury | Drug Induced Liver Injury Rank (DILIrank 2.0)TemozolomidevLess-DILI-concern4Adverse reactionsDOI:10.1016/j.drudis.2016.02.015 |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during Lactation |
| Wassergefährdungsklasse (WGK) | 3 |
| Zollcode | 29339900 |
| RTECS-Nr. | NJ5927050 |
| R-Sätze (R) | 45-46-60-61-22-36/37/38 |
| Gefahrensymbole | T,Xi |
| Sicherheitshinweise (S) | 24/25-45-36/37-26-53-36 |
| Lagerklasse | 6.1C - Combustible acute toxic Cat.3toxic compounds or compounds which causing chronic effects |
| Gefahrenklasse | Acute Tox. 4 OralCarc. 1BEye Irrit. 2Muta. 1BRepr. 1BSkin Irrit. 2STOT SE 3 |
Anwendungen & Verwendung
Beschreibung
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.
Verwenden
Temozolomide is an antineoplastic drug and an Imidazotetrazine alkylating agent. It induces apoptosis and causes cell cycle arrest at the G2/M checkpoint. It rapidly degrades in the body, producing the active metabolite MTIC, which exerts an anti-tumor effect. Moreover, temozolomide has shown effectiveness against paclitaxel-resistant tumors and has been utilized in the study of drug resistance mechanisms in glioblastoma cell lines.
Herstellung & Synthese
synthetische
The synthesis of temozolomide involves several steps. First, 5-Amino-4-imidazolecarboxamide is diazotized using nitrite. Then, the diazotized compound is reacted with methyl isocyanate in dichloromethane. This reaction leads to the cyclization of the compound, ultimately resulting in the formation of temozolomide.