Stereospecific synthesis of chiral metabolites of ifosfamide and their determination in the urine

Abstract

The stereospecific synthesis of two chiral metabolites of ifosfamide (2), 4-ketoifosfamide (5) and 2-amino-3-(2-chloroethyl)tetrahydro-2H-1,3, 2-oxazaphosphorine 2-oxide (9), is reported. The absolute configuration of both compounds was assigned on the basis of chemical correlation. In addition, two other achiral metabolites of 2, carboxyifosfamide (6) and IPAM (7), were synthesized. These and other organophosphorus metabolites of ifosfamide were found, by 31P NMR, in the urine of patients to whom racemic 2 was administered. The measurements performed in the presence of optically active lanthanide shift reagent [Eu(tfc)3] showed considerable stereoselectivity of in vivo formation of some chiral metabolites of ifosfamide.

Fluorine-19 or phosphorus-31 NMR spectroscopy: A suitable analytical technique for quantitative in vitro metabolic studies of fluorinated or phosphorylated drugs

“…31 P NMR is used to analyse urine samples from patients treated with CP [20,25,88] or IF [23,24,89,90] and also plasma and cerebrospinal (CSF) samples from a few patients treated with IF [23].…”

“…In a pioneering study, Misiura et al [89] use 31 P NMR to quantify the urinary excretion of IF and its metabolites CXIF, DCCP, 2-DECLIF and KetoIF whose attribution is questionable with a poor-performing 60 MHz spectrometer (24.3 MHz 31 P resonance frequency).…”

Sulfonyl-Containing Aldophosphamide Analogues as Novel Anticancer Prodrugs Targeted against Cyclophosphamide-Resistant Tumor Cell Lines

“…The filtrate was evaporated in vacuo to yield a viscous, yellow oil. The crude product was purified on a flash column with eluent EtOAc to give 1.4 g (22% yield) of 4 as a yellow oil: TLC R f 0.53 in EtOAc; 1 2-(Methylsulfonyl)ethyl N,N-bis(2-chloroethyl)phosphorodiamidate (6) was synthesized according to published procedure 39 with some modifications. A solution of 2-(methylsulfonyl)ethanol (3.72 g, 30 mmol) and triethylamine (3.10 g, 30 mmol) in CH 2Cl2 (30 mL) was added dropwise to a solution of phosphorus oxychloride (4.60 g, 30 mmol) in CH2Cl2 (50 mL) at ice-bath temperature over a 20 min period.…”

Phosphorothioate Nucleotides and Oligonucleotides – Recent Progress in Synthesis and Application

“…It Scheme 3 was assumed that in nucleoside monomers possessing the 2-thioxo-1,3,2-oxaselena phospholane moiety, the PÀSe bond would be more labile (a SeÀR moiety is a better leaving group than a SÀR one) allowing for higher yields, possibly using weaker bases than DBU. However, it was found that the reactivity of the 1,3,2-oxaselenaphospholane monomer in the presence of activators of lower basicity than DBU was reduced [97]. This indicates that the ring opening does not depend on the quality of the leaving group, but rather on the concentration of an alkoxide nucleophile formed from the 5'-OH group.…”