Temozolomide

Bezeichnung:Temozolomide

CAS-Nr85622-93-1

Englisch Name:Temozolomide

CBNumberCB2708199

SummenformelC6H6N6O2

Molgewicht194.15

MOL-Datei85622-93-1.mol

Temozolomide physikalisch-chemischer Eigenschaften

Schmelzpunkt	212°C dec.
Siedepunkt	526.6±42.0 °C(Predicted)
Dichte	1.97±0.1 g/cm3(Predicted)
storage temp.	2-8°C
Löslichkeit	DMSO: soluble10mg/mL, clear
pka	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.
InChIKey	BPEGJWRSRHCHSN-UHFFFAOYSA-N
CAS Datenbank	85622-93-1(CAS DataBase Reference)

Sicherheit

Kennzeichnung gefährlicher	T,Xi
R-Sätze:	45-46-60-61-22-36/37/38
S-Sätze:	24/25-45-36/37-26-53-36
WGK Germany	3
RTECS-Nr.	NJ5927050
HS Code	29339900

Gefahreninformationscode (GHS)

Temozolomide Chemische Eigenschaften,Einsatz,Produktion Methoden

R-Sätze Betriebsanweisung:
R45:Kann Krebs erzeugen.
R46:Kann vererbbare Schäden verursachen.
R60:Kann die Fortpflanzungsfähigkeit beeinträchtigen.
R61:Kann das Kind im Mutterleib schädigen.
R22:Gesundheitsschädlich beim Verschlucken.
R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
S-Sätze Betriebsanweisung:
S24/25:Berührung mit den Augen und der Haut vermeiden.
S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn möglich, dieses Etikett vorzeigen).
S36/37:Bei der Arbeit geeignete Schutzhandschuhe und Schutzkleidung tragen.
S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
S53:Exposition vermeiden - vor Gebrauch besondere Anweisungen einholen.
S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.
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.
Chemische Eigenschaften
Off-white to light-pink crystalline solid, crystallized from dichloromethane, melting point 212℃ (decomposition). Maximum UV absorption (in 95% ethanol): 327nm.
Originator
CRC Technology (UK)
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.
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.
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.
Manufacturing Process
Reaction of 1H-imidazole-4-carboxilic acid amide with nitrous acid leads to the diazonium salt (5-diazenyl-1-H-imidazole-4-carboxilic acid amide). Condensation of the diazonium salt with methylisocyanate leads to initial formation of unstable urea which cyclizes under the reaction condition to give 3,4-dihydro-3-methyl-4-oxoimidazo(5,1-d)-1,2,3,5-tetrazine-8-carboxamide (temozolomide).
Trademarks
Temodar (Schering);Temodal.
Therapeutic Function
Antineoplastic
Allgemeine Beschreibung
Temozolomide can be called as an oral alkylating agent and antitumour drug, which may show potent activity in the treatment of recurrent gliomas or glioblastoma, a kind of tumour that affects the brain or spine.
Biologische Aktivität
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).
Biochem/physiol Actions
Temozolomide is a DNA methylating agent and drug resistance-modifying agent; anti-tumor and anti-angiogenic. Temozolomide induces G2/M arrest and apoptosis through adduction of a methyl group to O6 position of guanine in genomic DNA and functional inactivation of DNA repair protein O(6)-alkylguanine DNA alkyltransferase (AGT) in base excision repair (BER) pathway.
Clinical Use
This imidazolotetrazine derivative is administered orally in capsule form for the treatment of glioblastoma multiforme or in patients with anaplastic astrocytoma who have not responded to procarbazine or the nitrosoureas.
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.
Stoffwechsel
Oral absorption is rapid and complete. The CYP450 enzymes are not extensively involved in temozolomide metabolism, and less than 6% of the drug is excreted unchanged in the urine. Women clear the drug less effectively than men and have a higher incidence of severe neutropenia and thrombocytopenia in the initial therapy cycle. Food decreases temozolomide absorption, and myelosuppression is the most significant adverse effect.
Lager
Store at RT
Einzelnachweise
1) Kurzen et al. (2003), Inhibition of angiogenesis by non-toxic doses of temozolomide; Anticancer Drugs, 14 515
2) Gunther et al. (2003), Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids; Br. J. Cancer, 88 463
3) Danson et al. (2001), Temozolomide: a novel oral alkylating agent; Curr. Opin. Expert Rev. Anticancer Ther., 10 13
4) Natsumeda et al. (2011), Induction of autophagy in temozolomide treated malignant gliomas; Neuropathology, 31 486

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