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A series of new imidazo5,1-d-1,2,3,5-tetrazinones with additional hydrogen-bonding or ionic substituents at the 8-carboxamide position of the antitumor drugs temozolomide (1) and mitozolomide (2) has been prepared. None of these compounds were significantly more cytotoxic in vitro against the mouse TLX5 lymphoma than the lead structures. Molecular modeling techniques have been used to design benzo- and pyrazolo4,3-d-1,2,3-triazinones bearing carboxamide groups in appropriate positions which are isosteric with temozolomide and mitozolamide but which cannot ring open to alkylating species. As predicted, these compounds have no inhibitory properties against human GM892A or Raji cell lines in vitro. Temozolomide and the spermidine-temozolomide conjugate 28 preferentially methylate guanines within guanine-rich sequences in DNA, but no experimental evidence has been found to support the hypothesis that such regions are involved in catalyzing the ring opening of the imidazotetrazinone prodrugs to their active forms.
Clark et al. (Sat,) studied this question.