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

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...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 1992-04, Vol.35 (8), p.1451-1457
Main Authors: Woo, Peter W. K, Kostlan, Catherine R, Sircar, Jagadish C, Dong, Mi K, Gilbertsen, Richard B
Format: Article
Language:English
Subjects:
Cell Line
Chemistry
Chemistry, Medicinal
Enzyme Inhibitors - chemical synthesis
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings
Humans
Hypoxanthines - chemical synthesis
Hypoxanthines - pharmacology
Immunosuppressive Agents - chemical synthesis
Life Sciences & Biomedicine
Organic chemistry
Pharmacology & Pharmacy
Preparations and properties
Purine-Nucleoside Phosphorylase - antagonists & inhibitors
Science & Technology
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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-mu-M; IC50 in MOLT-4 assay, 204.2-mu-M) 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 analogous 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).
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00086a014