Abstract
Several modifications of 1-??-D-arabinosylcytosine (ara-C) are described with particular attention to increasing residence time in tissues and lowering toxicity. Precursors containing an isourea-ether or amidine group and a phosphate group were synthesized and studied in vitro. The most promising compound satisfying these requirements is O??:2'-anhydro-1-??-D-arabinosylcytosine 3'-phosphate (anhydro-ara-CMP). The disappearance of the anhydro-ara-C chromophore was followed spectrophotometrically in phosphate, bicarbonate, citrate and lactate buffers of various concentrations and pH. The change in ultraviolet absorbance was found to be due to two concomitant first-order reactions. The main reaction was a general base catalyzed hydrolysis leading to the formation of 1-??-D-arabinosylcytosine 3'-phosphate (ara-CMP), but the formation of cytidine 2':3'-cyclic phosphate (2':3'-CMP) was also observed to some extent. The rate constants and the ribo to arabino ratio depended on the ionic strength and the pH. In the course of studies of ???ü?C-labeled compound in heparin-treated human blood in vitro, the presence of ara-C and its favorable rate of formation was observed. It was concluded that the administration of a single dose of anhydro-ara-CMP will produce an effect similar to a continuous infusion of low concentrations of ara-C. On the basis of comparative dephosphorylation rates of anhydro-ara-CMP, ara-CMP, cytidine 5'-phosphate and cytidine 3'-phosphate with Escherichia coli alkaline phosphatase and potato acid phosphatases, it was also concluded that the phosphate group would only afford minimal protection against deamination. Binding studies of anhydro-ara-C with bovine-??-lactoglobulin A, bovine serum albumin and calf thymus histone f2a2, using the equilibrium dialysis technique, showed that electrostatic binding of the positively charged anhydro-ara-C could take place with negatively charged blood serum proteins. ...
Hayashikawa, Robert Hideo (1973). Studies on some pyrimidine nucleotides. Doctoral dissertation, Texas A&M University. Texas A&M University. Libraries. Available electronically from
https : / /hdl .handle .net /1969 .1 /DISSERTATIONS -156322.