The partitioning of phosphoramide mustard and its aziridinium ions among alkylation and P-N bond hydrolysis reactions

Ellen M. Shulman-Roskes, Dennis A. Noe, Michael P. Gamcsik, Allison L. Marlow, John Hilton, Frederick H. Hausheer, O. Michael Colvin, Susan M. Ludeman

Research output: Contribution to journalArticle

Abstract

NMR (1H and 31P) and HPLC techniques were used to study the partitioning of phosphoramide mustard (PM) and its aziridinium ions among alkylation and P-N bond hydrolysis reactions as a function of the concentration and strength of added nucleophiles at 37 °C and pH 7.4. With water as the nucleophile, bisalkylation accounted for only 10-13% of the product distribution given by PM. The remainder of the products resulted from P-N bond hydrolysis reactions. With 50 mM thiosulfate or 55-110 mM glutathione (GSH), bisalkylation by a strong nucleophile increased to 55- 76%. The rest of the PM was lost to either HOH alkylation or P-N bond hydrolysis reactions. Strong experimental and theoretical evidence was obtained to support the hypothesis that the P-N bond scission observed at neutral pH does not occur in the parent PM to produce nornitrogen mustard; rather it is an aziridinium ion derived from PM which undergoes P-N bond hydrolysis to give chloroethylaziridine. In every buffer studied (bis-Tris, lutidine, triethanolamine, and Tris), the decomposition of PM (with and without GSH) gave rise to 31P NMR signals which could not be attributed to products of HOH or GSH alkylation or P-N bond hydrolysis. The intensities of these unidentified signals were dependent on the concentration of buffer.

Original languageEnglish (US)
Pages (from-to)515-529
Number of pages15
JournalJournal of Medicinal Chemistry
Volume41
Issue number4
DOIs
StatePublished - Feb 12 1998
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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    Shulman-Roskes, E. M., Noe, D. A., Gamcsik, M. P., Marlow, A. L., Hilton, J., Hausheer, F. H., Colvin, O. M., & Ludeman, S. M. (1998). The partitioning of phosphoramide mustard and its aziridinium ions among alkylation and P-N bond hydrolysis reactions. Journal of Medicinal Chemistry, 41(4), 515-529. https://doi.org/10.1021/jm9704659