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Potentiation of 2'-Deoxyguanosine Cytotoxicity by a Novel Inhibitor of Purine Nucleoside Phosphorylase, 8-Amino-9-benzylguanine¹

Departments of Internal Medicine [D.S.S., P.E.D.], Biological Chemistry [P.E.D.], and Medicinal Chemistry [J-W.C., K.E.P., L.B.T.], University of Michigan, Ann Arbor, Michigan 48109

We have synthesized and evaluated a series of 9-substituted analogues of 8-aminoguanine, a known inhibitor of human purine nucleoside phosphorylase (PNP) activity. The ability of these agents to inhibit PNP has been investigated. All compounds were found to act as competitive (with inosine) inhibitors of PNP, with K_i values ranging from 0.2 to 290 µM. The most potent of these analogues, 8-amino-9-benzylguanine, exhibited a K_i value that was 4-fold lower than that determined for the parent base, 8-aminoguanine. As a metabolically stable compound in human blood, 8-amino-9-benzylguanine was more effective than 8-aminoguanine at potentiating the toxicity of 2'-deoxyguanosine to MOLT-4 T-lymphoblasts in culture. 8-Amino-9-benzylguanine is the most potent base or nucleoside inhibitor of human PNP reported to date, and it is a promising lead compound in the development of more effective PNP inhibitors.

¹ This investigation was supported by Public Health Service grants CA-26284 (P. E. D.) and CA-28381 (L. B. T.) awarded by the National Cancer Institute, Department of Health and Human Services, and aided by grant CH-299 (L. B. T.) from the American Cancer Society.

² Arthritis Foundation Fellow.

³ To whom requests for reprints should be addressed, at the Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109.

Received 8/15/85. Revised 10/23/85. Accepted 10/25/85.

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