114601-31-9Relevant articles and documents
Antitumor Imidazotetrazines. 35. New Synthetic Routes to the Antitumor Drug Temozolomide
Wang, Yongfeng,Stevens, Malcolm F. G.,Chan, Tze-Ming,DiBenedetto, Donald,Ding, Zhe-Xing,Gala, Dinesh,Hou, Donald,Kugelman, Max,Leong, William,Kuo, Shen-Chun,Mas, Janet L.,Schumacher, Doris P.,Shutts, Bruce P.,Smith, Lyman,Zhan, Zheng-Yun J.,Thomson, William T.
, p. 7288 - 7294 (1997)
Three new pathways to the antitumor drug temozolomide (4) have been explored via intermediates 3, 6, and 7. The key intermediate 5-amino-1-(N-methylcarbamoyl)imidazole-4-carboxamide (6) has been successfully converted to 4 in 45% yield by employing sodium nitrite in aqueous tartaric acid at 0-5°C. Compound 6 is prepared from nitrophenyl carbamate 14a and methylamine or directly from 5-aminoimidazole-4-carboxamide (13) and either methyl isocyanate or N-methylcarbamoyl chloride. Temozolomide (4) is also prepared from 8-cyano-3-methylimidazo[5,1-d]-l,2,3,5-tetrazin4(3H)-One (7) by hydrolysis to the hydrochloride salt of 4 in 10 M hydrochloric acid. Compound 7 is prepared from either 5-diazoimidazole-4-carbonitrile (28) and methyl isocyanate or by diazotization of 5-amino-1-(N-methylcarbamoyl)imidazole-4-carbonitrile (25). Attempts to cyclize 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (3) with phosgene or phosgene equivalents were unsuccessful: only 2-azahypoxanthine (11) was isolated.
Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma
Svec, Riley L.,Furiassi, Lucia,Skibinski, Christine G.,Fan, Timothy M.,Riggins, Gregory J.,Hergenrother, Paul J.
, p. 3206 - 3216 (2018/11/30)
Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), a small molecule DNA alkylating agent, remains the standard-of-care for glioblastoma (GBM). TMZ has an unusual mode-of-action, spontaneously converting to its active component via hydrolysis in vivo. While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression. TMZ was first synthesized in 1984, but certain key derivatives have been inaccessible due to the chemical sensitivity of TMZ, precluding broad exploration of the link between imidazotetrazine structure and biological activity. Here, we sought to discern the relationship between the hydrolytic stability and anticancer activity of imidazotetrazines, with the objectives of identifying optimal timing for prodrug activation and developing suitable compounds with enhanced efficacy via increased blood-brain barrier penetrance. This work necessitated the development of new synthetic methods to provide access to previously unexplored functionality (such as aliphatic, ketone, halogen, and aryl groups) at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 h), we derive a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM. This work points a clear path forward for the development of novel and effective anticancer imidazotetrazines.
A new synthesis of temozolomide
Wanner, Martin J.,Koomen, Gerrit-Jan
, p. 1877 - 1880 (2007/10/03)
An efficient condensation reaction for the synthesis of phenyloxycarbonyl substituted triazenylimidazoles was described. The condensation reaction made use of nitrosoimidazoles and phenyl methylcarbazate as the reacting products. The exposure of the triazenes to diffuse daylight induced the isomerization of the triazene-nitrogen bonds, resulting in a high yield of temozolomide.
