Triazenes

Dacarbazine (DTIC) is employed in combination therapy for the treatment of metastatic malignant melanoma and Hodgkin's disease. This compound was initially designed as an antimetabolite since it is an analog of 5-aminoimidazole-4-carbox-amide, an intermediate in purine biosynthesis. However, its cytotoxic activity is due to the generation during its metabolism of methyldiazonium, which methylates DNA.53 Methyldiazonium has a half-life of about 0.4 s in aqueous solution, which is sufficient to allow it to reach its target. A mechanism for this process is summarized in Fig. 5.29, where activation of dacarbazine by metabolic oxidative demethylation to 5.46 (5-methyltriazenoimidazole-4-carboxamide, MTIC) was proved by the isolation of labeled formaldehyde and 5-aminoimidazole-4-carboxamide (AIC) when dacar-bazine was labeled with 14C at one of the methyl groups. Intermediate 5.46 is then transformed by tautomerism into 5.47, a diazonium precursor. The major methyla-tion reaction takes place at the guanine N-7 atom, and is relatively nontoxic. Meth-ylation at guanine O-6 also occurs, and is thought to be the main cytotoxic mechanism.54 It is interesting to note that compounds that act as precursors to the ethyldiazonium cation lack any DNA binding properties, which has been explained by the lower stability in aqueous solution of ethyldiazonium with regard to methyl-diazonium,55 leading to its evolution to ethylene by elimination or to ethanol by reaction with a molecule of water before reaching DNA.

Besides its toxicity, dacarbazine has several drawbacks because of its hydrophilicity, which leads to slow and incomplete oral absorption and therefore intravenous administration becomes necessary. Another disadvantage is its high photosensitivity, with a very short half-life (about 30 min), decomposing to 2-azahypoxanthine via an intermediate diazonium species (Fig. 5.30). For this reason, intravenous infusion bags of dacarbazine must be protected from light.

H2N-OC

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