title: Identification of new aqueous chemical degradation products of isophosphoramide mustard.
abstract: NMR (31P, 1H and 13C) spectroscopy was used to study the products of the degradation of isophosphoramide mustard (IPM) in buffered solutions at pH ranging from 1 to 13. At pH < or = 1, the only degradation compounds detected were phosphate ion (Pi) and chloroethylammonium chloride (CEA-HCl), resulting from the breakdown of the two P-N bonds (pathway Ia). At pH 9.3 and 13, only the products of 1,3-cyclization of the N-chloroethyl group (monoaziridinylIPM (monoAzIPM) and a very low level of bisaziridinylIPM (bisAzIPM)) were found after approximately 15 h of reaction (pathway II). At intermediate pH, the two pathways coexist. At pH 3.5 and 5.0, the P-N bond hydrolysis is the major pathway, but two final phosphorylated products were detected, Pi which represented 67% (pH 3.5) and 17% (pH 5.0) of all the IPM phosphorylated degradation products after approximately 15 h of reaction, and phosphorylethanolamine (PEA) which represented 16% (pH 3.5) and 46% (pH 5.0) of the same sum. PEA formation can be explained by the 1,5-cyclization of a transient compound giving a 1,3,2-oxazaphospholidine intermediate whose P-N bond is exclusively cleaved in acidic medium. The presence of monohydroxyIPM (monoOHIPM) (whose percentage increases with pH from 5% (pH 3.5) to approximately 28% (pH 5.0) of all the IPM phosphorylated degradation compounds), probably coming from the alkylation by water of an aziridine/aziridinium intermediate, demonstrates the occurrence of pathway II. At pH 7.0 and 7.4, the pathway II is initiated first, leading to 1,3-cyclization(s), followed by water alkylation of the aziridines formed. The sequences are IPM 1-->monoAzIPM 5-->bisAzIPM 9; IPM 1-->monoAzIPM 5-->monoOHIPM 6-->monoAzIPM with a N-hydroxyethylchain (presumed structure) 7-->dihydroxyIPM 8. Nevertheless, PEA and Pi are the final products observed, which implies the P-N bond hydrolysis of products 5-9 as demonstrated by the presence in the medium of CEA, aziridine and ethanolamine.
authors.affiliation: Groupe de RMN Biomédicale, Laboratoire des IMRCP, Université Paul Sabatier, 118, route de Narbonne, 31062, Toulouse, France.
authors.forename: S
authors.initials: S
authors.lastname: Breil
authors.forename: R
authors.initials: R
authors.lastname: Martino
authors.forename: V
authors.initials: V
authors.lastname: Gilard
authors.forename: M
authors.initials: M
authors.lastname: Malet-Martino
authors.forename: U
authors.initials: U
authors.lastname: Niemeyer
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D010752:Phosphoramide Mustards / Q000737:chemistry*; D012996:Solutions
chemical_list: D018906:Antineoplastic Agents, Alkylating; D010752:Phosphoramide Mustards; D012996:Solutions; C027061:isophosphamide mustard