Compounds containing the 3-amino-1,2,4-benzotriazine 1,4-dioxide core are hypoxia selective bioreductively-activated drugs that kill oxygen-poor cells found in solid tumors.  In the parent drug tirapazamine, the one-electron reduced drug radical mediates oxidative DNA damage, while the two-electron reduced mono-N-oxide is an inactive metabolite.  Here we describe tirapazamine analogues in which the mono-N-oxide metabolite is an activated DNA cross-linking agent.  Agents of this type potentially posses increased hypoxia-selective cell killing properties.

Tirapazamine as a molecular switch for cellular hypoxia: Grafting nitrogen mustard chemistry onto the 1,2,4-benzotriazine 1,4-dioxide core

244th National Meeting (2012)

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