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Some Metabolic Properties of Nucleotides of 1-ß-D-Arabinofuranosylcytosine^*

Paul T. Cardeilhac and Seymour S. Cohen

( Department of Biochemistry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania)

Arabinosylcytosine¹ is a compound markedly inhibitory to the multiplication of many animal tumor cells and of viruses containing deoxyribonucleic acid. 5'-Nucleotides have been prepared and studied for possible incorporation into polynucleotides. Arabinosylcytosine mono-, di-, and triphosphates were synthesized by both chemical and enzymatic methods. Labeled and unlabeled arabinosylcytosine nucleotides were tested for their capacity to serve as substrates for purified polynucleotide phosphorylase, deoxyribonucleic acid-dependent ribonucleic acid polymerase, deoxyribonucleic acid polymerase, and the enzyme which incorporates adenosine monophosphate and cytidine monophosphate into amino acid acceptor ribonucleic acid. The inhibitory effects of these nucleotides were also determined on these enzymes. Arabinosylcytosine diphosphate was found to be completely inert as a substrate for polynucleotide phosphorylase, although it strongly inhibited the polymerization of adenosine diphosphate and cytidine diphosphate into polyadenylate and polycytidylate, respectively. In mixtures having 15 moles of arabinosylcytosine diphosphate to 85 moles of adenosine diphosphate or cytidine diphosphate, polymerization of the diphosphate substrates catalyzed by polynucleotide phosphorylase was inhibited by more than 95 per cent. No incorporation of tritium-labeled arabinosylcytosine nucleotides was detected in the ribonucleic acid or deoxyribonucleic acid synthesized in the presence of the labeled compounds. Thus, tritiated arabinosylcytosine triphosphate was found to be less than 1 per cent as effective a substrate as cytidine triphosphate for ribonucleic acid polymerase, deoxycytidine triphosphate for deoxyribonucleic acid polymerase, and cytidine triphosphate for the enzyme incorporating adenosine monophosphate and cytidine monophosphate into amino acid acceptor ribonucleic acid. No marked inhibition of these enzymes was produced by arabinosylcytosine triphosphate in amounts equal to the cytidine triphosphate or deoxycytidine triphosphate present. The absence of incorporation of arabinosylcytosine into polynucleotides tends to eliminate some significant potential toxicities in the development of chemotherapy with this compound.

^* The data in this paper are taken from a dissertation presented by Paul T. Cardeilhac to the faculty of the Graduate School of Arts and Sciences of the University of Pennsylvania in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

¹ The abbreviations used are: arabinosylcytosine, 1-ß-D-arabinofuranosylcytosine; ara-CMP, 1-ß-D-arabinofuranosylcytosine-5'-phosphate; aza-UDP, 6-aza-uridine-5'-diphosphate; MDP, 6-thioinosine-5'-diphosphate.

The research of one of the investigators (P. T. C.) was supported by Grant ADP-14, 727-C1 of the U. S. Public Health Service. Present address: Department of Physiology, Oklahoma State University, Stillwater, Oklahoma.

Received 3/20/64.