Studies on the side-chain hydroxylation of ifosfamide and its bromo analogue

Abstract

Deutero-substituted (α,α,α′,α′-tetradeuterated) derivatives of ifosfamide (IF-d4) and its bromo analogue were synthesised. In vitro metabolic studies showed that microsomal hydroxylation of IF-d4 is slower than for unlabelled compound, suggesting that kinetic isotope effect operates during those transformations. At the same time deutero-substituted derivatives are more active against L1210 leukaemia in mice than unlabelled compounds, suggesting a negative role of side-chain hydroxylation metabolic pathways in the anticancer activity of ifosfamide and its analogues. © 2002 Elsevier Science Ltd. All rights reserved.