title: Comparison of the protonation of isophosphoramide mustard and phosphoramide mustard.
abstract: The alkylating agent isophosphoramide mustard (IPM) spontaneously forms a relatively stable aziridine derivative which can be directly observed using NMR spectroscopy. The protonations of IMP and its aziridine were probed using 1H, 31P, 15N, and 17O NMR spectroscopy. The positions of the 31P, 15N, and 17O resonances of IPM between pH 2 and 10 each exhibit a single monobasic titration curve with the same pKa of 4.31 +/- 0.02. On the basis of a comparison with other compounds and our earlier work with phosphoramide mustard, the NMR results for IPM indicate that protonation occurs at nitrogen and not oxygen. Over this same pH range, each of the 1H, 31P, and 15N resonances of IPM-aziridine also show a single monobasic titration with a pKa of 5.30 +/- 0.09. The magnitude of the change in chemical shifts suggests that the protonation of the IPM-aziridine occurs at the ring nitrogen. Theoretical gas-phase calculations of PM, IPM, and IPM-aziridine suggest O-protonation to be more likely; however, aqueous phase calculations predict the N-protonated forms to be most stable. Furthermore, for PM and IPM-aziridine, which contain nonequivalent nitrogens, the theoretical calculations and experimental data both agree as to which nitrogen undergoes protonation. These results suggest that the IMP-aziridine remains unprotonated under physiological conditions and may, in part, explain the lower alkylating activity of IPM as compared to PM.
authors.affiliation: Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: K K
authors.initials: KK
authors.lastname: Millis
authors.forename: M E
authors.initials: ME
authors.lastname: Colvin
authors.forename: E M
authors.initials: EM
authors.lastname: Shulman-Roskes
authors.forename: S M
authors.initials: SM
authors.lastname: Ludeman
authors.forename: O M
authors.initials: OM
authors.lastname: Colvin
authors.forename: M P
authors.initials: MP
authors.lastname: Gamcsik
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D010752:Phosphoramide Mustards / Q000737:chemistry*; D011522:Protons; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D010752:Phosphoramide Mustards; D011522:Protons; C030090:phosphoramide mustard; C027061:isophosphamide mustard; D007069:Ifosfamide