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5-Methyltriazenoimidazole 4-carboxamide (MTIC) 5.46

FIGURE 5.31 Temozolomide hydrolysis.

These problems have stimulated the synthesis of dacarbazine analogs, the most important of which is temozolomide. This compound is one of the few drugs specifically approved for a brain tumor, namely anaplastic astrocytoma, and the first that can be administered orally. It is converted into the same intermediate 5.46 (MTIC) generated by dacarbazine, but in the case of temozolomide the bioactiva-tion process involves a non-enzymatic hydrolysis reaction followed by spontaneous decarboxylation (Fig. 5.31). The absence of hepatic activation is an advantage because metabolic individual variation in patient microsomal activity need not be taken into account. The main problem associated with temozolomide administration is bone marrow toxicity. The development of temozolomide is associated to the Universities of Nottingham, Aston, and Strathclyde and started as a purely synthetic project related to the chemistry of imidazotetrazines, but screening studies identified some of the compounds as promising anticancer targets.

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