1,2,4-Benzotriazine 1,4-dioxides. An important class of hypoxic cytotoxinswith antitumor activity

Tirapazamine (1,2,4-benzotriazin-3-amine 1,4-dioxide, SR 4233, WIN 59075) i s the lead compound representing this class of anticancer drugs. It is also the first compound to be introduced in the clinic as a pure bioreductive c ytotoxic agent. Tirapazamine represents a completely novel approach to the treatment of solid tumors and has generated considerable interest, with res earch being carried out on all aspects of the its anticancer activity. Phas e III trials of tirapazamine in combination with cisplatin (cDDP) have rece ntly been concluded, and phase II trials of tirapazamine in combination wit h irradiation are presently being performed. We developed a drug discovery program into this class of compounds designed to produce derivatives with i mproved in vivo activity against solid tumors. Based on the hypothesis that these compounds require bioreductive activation for antitumor activity, th e research was primarily directed at producing analogues with greater elect ron affinity and improved aqueous solubility. The in vitro and in vivo data for a variety of structural analogues clearly show that 1,2,4-benzotriazin e I,4-dioxides have considerable potential as anticancer agents. When their activity is compared directly with the activity observed for tirapazamine, the most promising series of analogues appears to be the 3-alkyl-substitut ed derivatives, especially the 3-ethyl- and 3-(2'-methoxyethyl)-derivatives , SR 4895 and SR 4941 respectively.