ADENOSINE-DEAMINASE INHIBITORS - STRUCTURE-ACTIVITY-RELATIONSHIPS IN 1-DEAZAADENOSINE AND ERYTHRO-9-(2-HYDROXY-3-NONYL)ADENINE ANALOGS

Adenosine deaminase (ADA) is the enzyme which catalyzes the irreversible deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. It is widely distributed in vertebrate tissues and is thought to be essential for proper functioning of mammalian cells. ADA inhibitors may have several clinical applications (i.e., in the chemotherapy of lymphoproliferative disorders, in the immunosuppresive therapy, in adenosine level modulation). Modification of the purine moiety of adenosine led to ADA inhibitors. In particular, 1-deazaadenosine (1, Ki = 0.66 muM) and its 2'-deoxy derivative (21, Ki = 0.19 muM) are the most potent in the series. Substitutions on the N6 amino group did not produce a decrease in activity only when small groups, as hydroxyl or methyl, were introduced. The presence of a chlorine atom in position 2 produced a decrease in ADA inhibitory activity. All these findings are in agreement with a direct interaction of the 1-deazapurine moiety with the catalytic site of ADA. Erythro-9-(2-hydroxy-3-nonyl) adenine (12, EHNA) and 3-deazaEHNA (14) are potent ADA inhibitors with Ki in the nanomolar range. Opening the pyrimidine ring of EHNA led to a series of erythro-1-(2-hydroxy-3-nonyl)imidazole derivatives which are still ADA inhibitors. In order to introduce additional simplification and to investigate the role of nitrogen atoms in the azole structure, a series of di-, tri-, and tetrazoles bearing the 2-hydroxy-3-nonyl chain have been synthesized and tested. The results indicated that the presence of N-3 in the azole ring is critical for the inhibitory activity and that the introduction of additional nitrogens led to compounds whose potency range accounts for a direct interaction with an inhibitory site of ADA.