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Inhibitors of Purine Nucleoside Phosphorylase: Effects of 9-Deazapurine Ribonucleosides and Synthesis of 5'-Deoxy-5'-iodo-9-deazainosine¹

Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912 [J. D. S., J. B. R., R. E. P.]; Roger Williams General Hospital, Providence, Rhode Island 02908 [M-Y. C.]; and Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [M-I. L., W-Y. R., R. S. K.]

9-Deazapurine ribonucleosides constitute a new class of noncleavable purine nucleoside phosphorylase inhibitors that have at least 30-fold greater affinity for the enzyme than the corresponding C-nucleosides of the formycin B series. 9-Deazaguanosine, 9-deazainosine, and 5'-deoxy-5'-iodo-9-deazainosine competitively inhibited human erythrocytic purine nucleoside phosphorylase with K_i values of 29, 20, and 1.8 x 10^-7 M. The last compound is the most potent nucleoside inhibitor of the enzyme presently available and its synthesis is described. In contrast, 7,9-dideaza-7-thiainosine is a very weak inhibitor of the enzyme.

When tested as an inhibitor of 2'-deoxyguanosine phosphorolysis in intact human erythrocytes and MOLT-3 human T-cell lymphoblastic leukemia cells, 5'-deoxy-5'-iodo-9-deazainosine was equipotent with 8-aminoguanosine (which is a precursor for 8-aminoguanine, K_i = 2 x 10^-7 M). Similarly, 5'-deoxy-5'-iodo-9-deazainosine and 8-aminoguanosine both potentiated the growth inhibition of human T-lymphocytic MOLT-3 cells by 2'-deoxyguanosine, reducing the 50% inhibitory concentration from 2 x 10^-5 to 2 x 10^-6 M.

¹ This work was supported by grants CH-7Z and CH-266 from the American Cancer Society and USPHS grants CA 13943 and CA 24634 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed.

Received 11/12/85. Accepted 12/30/85.