28741-76-6Relevant articles and documents
Inhibitors of Human Purine Nucleoside Phosphorylase. Synthesis and Biological Activities of 8-Amino-3-benzylhypoxanthine and Related Analogues
Woo, Peter W. K.,Kostlan, Catherine R.,Sircar, Jagadish C.,Dong, Mi K.,Gilbertsen, Richard B.
, p. 1451 - 1457 (2007/10/02)
A series of 3-substituted hypoxanthines (6-10, 14-17) and related analogues (22, 23) have been synthesized as inhibitors of purine nucleoside phosphorylase (PNP), which may conceivably act as T-cell-selective immunosuppressive agents with potential utility in autoimmune disorders such as rheumatoid arthritis, in organ transplantations, and in T-cell leukemias.The compounds were evaluated for their PNP activity by a radiochemical assay and also for their cytotoxic effects on a T-lymphoblastoid cell line (MOLT-4).Appropriate substitutions on 3-benzylhypoxanthine (7a) (IC50 in PNP assay, 112 μM; IC50 in MOLT-4 assay, 204.2 μM) increase potency: 8-amino (17a; 42.6, 65.2), 2-hydroxy (9a; 13.4, 28.6), 2-amino (10a; 11.4, 29.1), and 2,8-diamino (16a; 5.0, 11.9).Variation of the 3-aryl substitutents of 16a as in 16b-d has thus far failed to further increase potency.Replacement of the 6-oxygen function in 7a with the analoguous nitrogen or sulfur functions, as in 22a and 23a, resulted in little change in activity.Other variations including the increase of the 3-aliphatic chain length as in 6h and 7h (n = 2), the substitution of the phenyl ring with electron-withdrawing groups as in 7e-g, and replacement of the 2-hydrogen with methylthio as in 8a and 14a resulted in decrease of activity.The values for 16a-d represent moderate but significant activities, as compared to the most active inhibitor presently known, 8-amino-9-thienylguanine (1c; 0.17, 0.82). 2,8-Diamino-3-substituted hypoxanthines (16a-d) represent a novel structural type hitherto unreported in the literature, and efficient methodologies for their synthesis were developed in the present studies.The formation of the aminoimidazole moiety occurred through a base-catalyzed 1,5-(O->N)-carbamimidoyl rearrangement (13 to 14, 20 to 16).
