The key role of hydroxylation for the cytostatic activity and selectivity of cyclophosphamide.

The "pro-drug" cyclophosphamide (CP) is activated by liver "mixed function" hydroxylases to 4-hydroxy-cyclophosphamide (4-OH-CP), which represents the cytostatically active principle. Since the primary metabolite 4-OH-CP retains all the specific pharmacological properties of the parent compound without the need of metabolic activation, it constituted the basic principle and rationale for further drug development. Due to its chemical instability, 4-OH-CP had to be stabilized through appropriate substitutions at the 4-position of the oxazaphosphorine ring. ASTA Z 7557, in which the side chain is a 2-mercapto-ethanesulfonate, represents the prototype of this new class of oxazaphosphorines.