7151-30-6Relevant academic research and scientific papers
NOVEL HYPOXANTHINE AND THIOHYPOXANTHINE COMPOUNDS
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Page 18, (2010/02/08)
Disclosed are compounds of formula (I) wherein R3, R6, R8 are as described herein. The compounds are effective selective PDE IV inhibitors.
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).
