The early success of the nitrogen mustards led researchers to investigate other compounds that contained a preformed aziri-dine ring, and thiotepa resulted from this work. Thiotepa containing the thiophosphoramide functionality was found to be more stable than the oxa-analog (TEPA) but is metabolically converted to TEPA by desulfuration in vivo.15 Thiotepa incorporates a less reactive aziridine ring compared with that formed in mechlorethamine. The adjacent thiophosphoryl is electron withdrawing and, therefore, reduces the reactivity of the aziridine ring system. Although thiotepa is less reactive than many other alkylating agents, it has been shown to form cross-links. This is believed to occur by sequential reactions of thiotepa itself with DNA (Scheme 10.8).16 Monoalkylation is also possible as a result of aziridine formation via hydrolysis of thiotepa. Thiotepa is also metabolized by oxidative desulfurization mediated by CYP2B1 and CYP2C11.17 The decreased stability of the resulting TEPA undergoes hydrolysis to give aziridine, which may function to monoalkylate

Waters Aqc Structure

Phosphoramide mustard

Scheme 10.5 • Metabolic and chemical activation of cyclophosphamide.

Detoxification Mesna
Scheme 10.6 • Detoxification of cyclophosphamide by mesna.

DNA.18 The conclusion that aziridine is the active alkylating agent once thiotepa has been converted to TEPA is based on the fact that when TEPA is incubated with DNA, no crosslinks are formed and only monoadducts are generated. The reactivity of aziridine generated by either route may be somewhat enhanced within cancer cells, where the pH is normally reduced 0.2 to 0.4 pH units resulting in an increase in reactivity toward nucleophilic attack.

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