Dacarbazine and its structural analogues: Systematic computational studies of the configurations, tautomers, tautomerization pathways and bimolecular nucleophilic substitution reaction mechanisms of Dacarbazine; a triazene containing anti-neoplastic agent

A monomethyltriazene is believed to be the active metabolite of triazene containing anti-neoplastic agents and is thought to methylate the O6-oxygen of guanine to form methylguanine. Methylguanine is believed to be responsible for the observed cytotoxic properties of triazene containing anti-neoplastic agents. Dacarbazine, a triazene containing anti-neoplastic agent, has been shown to be the single most active agent for the treatment of malignant melanoma. Computational studies, including conformational and tautomer analysis, tautomerization pathways and a model mechanism of action, were conducted in the hopes that a better understanding of the chemical and physical properties of triazene containing anti-neoplastic compounds could be provided. This study found that the tautomerization of a monomethyltriazene is a relatively low energy process and the tautomer form will preferentially undergo an SN2 type reaction. It is proposed that following demethylation DTIC would preferentially undergo tautomerization followed by an SN2 type reaction to form methylguanine.