Inhibitors of human purine nucleoside phosphorylase. Synthesis and biological activities of 8-amino-3-benzylhypoxanthine and related analogues.

Abstract

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 microM; IC50 in MOLT-4 assay, 204.2 microM) 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 substituents 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).

• Authors: P W Woo, C R Kostlan, J C Sircar, M K Dong, R B Gilbertsen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 35 Issue 8 Pg. 1451-7 (Apr 17 1992) ISSN: 0022-2623 [Print] United States
• PMID: 1573639 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Hypoxanthines
• Immunosuppressive Agents
• 8-amino-3-benzylhypoxanthine
• Purine-Nucleoside Phosphorylase

Topics

• Cell Line
• Enzyme Inhibitors (chemical synthesis)
• Humans
• Hypoxanthines (chemical synthesis, pharmacology)
• Immunosuppressive Agents (chemical synthesis)
• Purine-Nucleoside Phosphorylase (antagonists & inhibitors)
• Structure-Activity Relationship