31P NMR and chloride ion kinetics of alkylating monoester phosphoramidates.
31P NMR spectroscopy was used to study the solvolysis kinetics of a novel series of alkylating monoester phosphoramidates (4a-d) under model physiologic conditions. Halide ion kinetics were used to determine the rate of aziridinium ion formation. The solvolysis rates showed the expected dependence upon substitution at the reactive nitrogen; comparison of 4a with phosphoramide mustard (1a) indicated that replacement of the amino group by alkoxy decreased the solvolysis rate by approximately 10-fold. The rate of conversion of starting compound (4a-d) to solvolysis product was essentially equal to the rate of halide ion release, suggesting that the aziridinium ion is a short-lived intermediate. 1H NMR and 31P NMR kinetics experiments performed in the absence and presence of trapping agent (dimethyldithiocarbamate) confirmed that the aziridinium ion was too short-lived to be observed via NMR. These compounds were also tested for cytotoxicity against L1210 leukemia and B16 melanoma cells in vitro; the monoalkylators 4c and 4d showed no activity, 4a was weakly cytotoxic, and 4b was comparable in activity to phosphoramide mustard.
Fries
K M
KM
Department of Chemistry, University of Rochester, New York 14642.
Borch
R F
RF
D000478:Alkylation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D002712:Chlorides; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D010752:Phosphoramide Mustards / Q000494:pharmacology* / Q000627:therapeutic use; D010758:Phosphorus; D013329:Structure-Activity Relationship
D002712:Chlorides; D010752:Phosphoramide Mustards; D010758:Phosphorus