The partitioning of phosphoramide mustard and its aziridinium ions among alkylation and P-N bond hydrolysis reactions.
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 degrees 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.
Shulman-Roskes
E M
EM
Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Noe
D A
DA
Gamcsik
M P
MP
Marlow
A L
AL
Hilton
J
J
Hausheer
F H
FH
Colvin
O M
OM
Ludeman
S M
SM
D000478:Alkylation; D001388:Aziridines / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D006859:Hydrogen; D006868:Hydrolysis; D007700:Kinetics; D008956:Models, Chemical; D019906:Nuclear Magnetic Resonance, Biomolecular; D010752:Phosphoramide Mustards / Q000737:chemistry*; D010758:Phosphorus; D013329:Structure-Activity Relationship
D001388:Aziridines; D010752:Phosphoramide Mustards; C030090:phosphoramide mustard; D010758:Phosphorus; D006859:Hydrogen