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, and its structural analogues

Abstract

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 S N 2 type reaction. It is proposed that following demethylation DTIC would preferentially undergo tautomerization followed by an S N 2 type reaction to form methylguanine.