Studies on the side-chain hydroxylation of ifosfamide and its bromo analogue.
Deutero-substituted (alpha,alpha,alpha',alpha'-tetradeuterated) derivatives of ifosfamide (IF-d(4)) and its bromo analogue were synthesised. In vitro metabolic studies showed that microsomal hydroxylation of IF-d(4) 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.
Misiura
Konrad
K
Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź , Poland. kmisiura@bio.cbmm.lodz.pl
Kinas
Ryszard W
RW
Kuśnierczyk
Halina
H
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000378:metabolism; D006900:Hydroxylation; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D007553:Isotope Labeling; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide