Clark A S, Deans B, Stevens M F, Tisdale M J, Wheelhouse R T, Denny B J, Hartley J A
Pharmaceutical Sciences Institute, Aston University, Aston Triangle, Birmingham, U.K.
J Med Chem. 1995 Apr 28;38(9):1493-504. doi: 10.1021/jm00009a010.
A series of new imidazo[5,1-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 pyrazolo[4,3-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.
已制备出一系列新型咪唑并[5,1 - d]-1,2,3,5 - 四嗪酮，它们在抗肿瘤药物替莫唑胺（1）和米托唑胺（2）的8 - 甲酰胺位置带有额外的氢键或离子取代基。这些化合物在体外对小鼠TLX5淋巴瘤的细胞毒性均未显著高于先导结构。分子建模技术已用于设计在适当位置带有甲酰胺基团的苯并和吡唑并[4,3 - d]-1,2,3 - 三嗪酮，它们与替莫唑胺和米托唑胺等电子，但不能开环形成烷基化物种。正如所预测的，这些化合物在体外对人GM892A或Raji细胞系没有抑制特性。替莫唑胺和亚精胺 - 替莫唑胺缀合物28优先使DNA中富含鸟嘌呤的序列内的鸟嘌呤甲基化，但尚未找到实验证据支持这样的假设，即这些区域参与催化咪唑并四嗪酮前药开环形成其活性形式。
