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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Further studies on the conversion of 4-hydroxyoxazaphosphorines to reactive mustards and acrolein in inorganic buffers.

The rates at which the 4-hydroxyoxazaphosphorines, 4-hydroxycyclophosphamide and 4-hydroxyifosfamide, are converted to reactive mustards and acrolein in phosphate and bicarbonate buffers were determined as a function of pH, ionic strength, temperature, and buffer concentration. Conversion was first-order with respect to both the 4-hydroxyoxazaphosphorine and phosphate or carbonate serving as a catalyst. The catalytic constant for dianionic phosphate-catalyzed conversion of 4-hydroxyifosfamide to isophosphoramide mustard and acrolein at 37 degrees was 0.189 min-1; a value of 0.194 min-1 M-1 was obtained when dianionic phosphate-catalyzed conversion of 4-hydroxycyclophosphamide to phosphoramide mustard and acrolein was examined. A catalytic constant of 3.09 min-1 M-1 was obtained for carbonate-catalyzed conversion of 4-hydroxycyclophosphamide to phosphoramide mustard and acrolein. Hydroxyl ion and water also catalyzed the reaction; catalytic constants were 2710 and 0.000006 min-1 M-1, respectively. The rate at which the 4-hydroxyoxazaphosphorines were converted to reactive mustards and acrolein in phosphate buffer increased as the pH, ionic strength, and temperature increased. The energy of activation was about 20 kcal/ mol. Dianionic phosphate, carbonate, hydroxyl ion, and water were apparently acting as general base catalysts of the rate-limiting step (probably the conversion of the intermediate aldehyde to the corresponding reactive mustard and acrolein) of the overall reaction, although specific base-general acid catalysis could not be ruled out. Bifunctional catalysis of the rate-limiting step did not appear to be significant and certainly was not obligatory as concluded previously by our laboratory. Assuming that the oncotoxic specificity of the oxazaphosphorines resides with the 4-hydroxyoxazaphosphorines and that their cytotoxic effect at therapeutic doses is largely mediated by the reactive mustards released within cells, these observations offer the possibility that intracellular general base catalytic activity serves as an important determinant with regard to the oncotoxic potential and specificity of the oxazaphosphorines. General base catalytic activity varies directly with pH, ionic strength, temperature, and the concentration of the base. The influence of some of these factors on the development of cyclophosphamide-induced bladder toxicity has already been demonstrated.[1]


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