ANTITUMOR IMIDAZOTETRAZINES .32. SYNTHESIS OF NOVEL IMIDAZOTETRAZINONES AND RELATED BICYCLIC HETEROCYCLES TO PROBE THE MODE OF ACTION OF THE ANTITUMOR DRUG TEMOZOLOMIDE

A series of new imidazo[5,1-d]-1,2,3,5-tetrazinones with additional hy drogen-bonding or ionic substituents at the 8-carboxamide position of the antitumor drugs temozolomide (1) and mitozolomide (2) has been pre pared. None of these compounds were significantly more cytotoxic in vi tro against the mouse TLX5 lymphoma than the lead structures. Molecula r modeling techniques have been used to design benzo- and pyrazolo[4,3 -d]-1,2,3-triazinones bearing carboxamide groups in appropriate positi ons which are isosteric with temozolomide and mitozolomide but which c annot ring open to alkylating species. As predicted, these compounds h ave no inhibitory properties against human GM892A or Raji cell Lines i n vitro. Temozolomide and the spermidine-temozolomide conjugate 28 pre ferentially methylate guanines within guanine-rich sequences in DNA, b ut no experimental evidence has been found to support the hypothesis t hat such regions are involved in catalyzing the ring opening of the im idazotetrazinone prodrugs to their active forms.