8-Aminoguanine is a potent inhibitor of purine nucleoside phosphorylase (PNP) and also a substrate of PNP. Two thioisosteres of 8-aminoguanine, 2, 5-diaminothiazolo [5, 4-d] pyrimidin-7 (6R)-one (2) and 2, 4-diaminothiazolo [4, 5-d] pyrimidin-7 (6H)-one (3), which cannot be substrates of PNP, were synthesized and evaluated for their inhibitory activity against PNP. They were found to be weak inhibitors of PNP and to be noncytotoxicfor MOLT-4 T-cells in culture.

Purine nucleoside phosphorylase (PNP) is a purine metabolizing enzyme that catalyzes the phosphorolysis of nucleosides such as (deoxy) inosine or (deoxy) guanosine to their respective bases and the corresponding l-(deoxy)-ribose phosphate. The reaction is a revesible one, ie PNP enzyme also catalyzes the formation of the nucleosides from the bases and l-(deoxy) ribose phosphate. PNP de-ficiency has been identified as a genetic defect associated with severe T-cell immune deficiency. 1" 4 5T-cells are the central element in the regulation of the immune system. Imbalance in T-cellfunction may be a major factor con-tributing to the development of autoimmune diseases. Proliferating T-cells are associated with certainautoim-mune diseases including rheumatoid arthritis and with transplant rejection and T-cell leukemia. Thus, PNP inhibitors have the potential to be useful as T-cell selective immunosuppressive agents for the treatment of autoim-mune diseases, for the prevention of transplant rejection, and also for the treatment of malignant lymphoprolifera-tive diseases. PNP inhibitors may also be useful in the treatment of insulin-dependent diabetes. 8-Aminoguanine (la) and 8-aminoguanosine6 7 (lb) have been identified as competitive inhibitors of human PNP that markedly potentiate the toxicity of 2'-deoxyguanosine for, and the accumulation of dGTP in, T lymphoblasts. 6" 8