title: 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.affiliation: Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: P W
authors.initials: PW
authors.lastname: Woo
authors.forename: C R
authors.initials: CR
authors.lastname: Kostlan
authors.forename: J C
authors.initials: JC
authors.lastname: Sircar
authors.forename: M K
authors.initials: MK
authors.lastname: Dong
authors.forename: R B
authors.initials: RB
authors.lastname: Gilbertsen
mesh_terms: D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D006801:Humans; D007042:Hypoxanthines / Q000138:chemical synthesis* / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000138:chemical synthesis; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007042:Hypoxanthines; D007166:Immunosuppressive Agents; C074206:8-amino-3-benzylhypoxanthine; D011683:Purine-Nucleoside Phosphorylase