The high reactivity of the epoxide ring toward nucleophilic groups in biomole-cules is the basis of the use of ethylene oxide to sterilize substances that would be damaged by heat, including medical supplies such as bandages, sutures, and surgical implements. It has also become quite common as a substructure in side chains of compounds aimed at alkylating DNA38 or other macromolecular targets.39

Diepoxybutane 5.30 is the simplest epoxide which is able to cross-link DNA. Although this compound is not employed as such, it is nonenzymatically generated from treosulfan, a member of the methanesulfonate family (see Section 5) that can be regarded as its prodrug, since this transformation (Fig. 5.20) is necessary for treosulfan cytotoxicity.40 Treosulfan alkylates DNA at guanine bases, very similar to nitrogen mustards, and is employed for the treatment of ovarian cancer.

Similarly, mitobronitol, the 1,6-dibromo analog of mannitol, is a bromohydrin prodrug that undergoes a double intramolecular nucleophilic displacement to give diepoxide 5.31, another DNA cross-linking reagent (Fig. 5.21). It is used for myelosuppression prior to allogeneic bone marrow transplantation in accelerated chronic granulocytic leukemia, showing lower toxicity than other alkylating agents such as busulfan.41

Mixed epoxide-aziridine antitumor compounds, such as the azinomycins, are also known. For instance, azinomycin B (carzinophilin), isolated from Streptomyces

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