689-98-5Relevant articles and documents
Chemical stability and fate of the cytostatic drug ifosfamide and its N- dechloroethylated metabolites in acidic aqueous solutions
Gilard, Véronique,Martino, Robert,Malet-Martino, Myriam,Niemeyer, Ulf,Pohl, J?rg
, p. 2542 - 2560 (2007/10/03)
31P NMR spectroscopy was used to study the products of the decomposition of the antitumor drug ifosfamide (IF, 1d) and its N- dechloroethylated metabolites, namely, 2,3-didechloroethylIF (1a) and 2- (1b) and 3-dechloroethylIF (1c), in buffered solutions at acidic pH. The first stage of acid hydrolysis of these four oxazaphosphorines is a P-N bond cleavage of the six-membered ring leading to the phosphoramidic acid monoesters (2a-d) of type R'HN(CH2)3OP(O)(OH)-NHR, with R and/or R' = H or (CH2)2Cl. The electron-withdrawing chloroethyl group at the endocyclic and/or exocyclic nitrogens counteracts the endocyclic P-N bond hydrolysis. This effect is even more marked when the N-chloroethyl group is in the exocyclic position since the order of stability is 1d > 1c > 1b > 1a. In the second stage of hydrolysis, the remaining P-N bond is cleaved together with an intramolecular attack at the phosphorus atom by the non-P-linked nitrogen of the compounds 2a-d. This leads to the formation of a 2- hydroxyoxazaphosphorine ring with R = H (3a coming from compounds 2a,c) or (CH2)2Cl (3b coming from compounds 2b,d) and to the release of ammonia or chloroethylamine. The third step is the P-N ring opening of the oxazaphosphorines 3a,b leading to the phosphoric acid monoesters, H2N(CH2)3OP(O)(OH)2 (4a) and Cl(CH2)2HN(CH2)3OP(O)(OH)2 (4b-1), respectively. For the latter compound, the chloroethyl group is partially (at pH 5.5) or totally (at pH 7.0) cyclized into aziridine (4b-2), which is then progressively hydrolyzed into an N-hydroxyethyl group (4b-3). Compounds 3a,b are transient intermediates, which in strongly acidic medium are not observed with 31P NMR. In this case, cleavage of the P-N bond of the type 2 phosphoramidic acid monoesters leads directly to the type 4 phosphoric acid monoesters. The phosphate anion, derived from P-O bond cleavage of these latter compounds, is only observed at low levels after a long period of hydrolysis. Compounds 1a-c and some of their hydrolytic degradation products (4b-1, 4b-2, diphosphoric diester [Cl(CH2)2NH(CH2)3OP(O)(OH)]2O (5), and chloroethylamine) did not exhibit, as expected, any antitumor efficacy in vivo against P388 leukemia. 31P NMR determination of the N- dechloroethylated metabolites of IF or its structural isomer, cyclophosphamide (CP), and their degradation compounds could provide an indirect and accurate estimation of chloroacetaldehyde amounts formed from CP or IF.
