| Abstract: | Several modifications of 1-β-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 O²:2'-anhydro-1-β-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-β-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 ¹⁴C-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-β-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. ... |
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