N

3. AZIRIDINES (ETHYLENEIMINES)

Since the active species involved in DNA alkylation by nitrogen mustards is an aziridinium cation, several aziridine derivatives were also tested as antitumor agents.

Electron-releasing substituents raise the aziridine nitrogen pKa and lead to a high concentration of aziridinium cations 5.20, which renders these compounds too reactive to be of therapeutic value. For this reason, the aziridine units are attached to electron-withdrawing groups, which reduce their reactivity as bases but still allow formation of DNA-alkylation products such as 5.22, which then are protonated to 5.21. The driving forces of this reaction are the stabilization of the nitrogen negative charge by the electron-withdrawing group and the liberation of ring strain on opening of the aziridium (Fig. 5.15).

Early studies showed that at least two aziridine units were necessary for good activity, which did not improve by addition of a third or fourth aziridine, suggesting that cytotoxicity is mainly due to a cross-linking mechanism, as in the case of nitrogen mustards. The first compounds of this family to be introduced in therapeutics were triethylenemelamine (TEM) and thiotepa, so called because it is a sulfur analog of triethylenephosphoramide (TEPA). Thiotepa is still used in bladder carcinoma by intracavitary administration because of its low stability in the acid conditions prevalent in the stomach. The previously discussed acid-assisted activation process is probably the main mechanism of DNA alkylation by these compounds.19

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