Adenosine deaminase inhibitors: Structure‐activity relationships in 1‐deazaadenosine and erythro‐9‐(2‐hydroxy‐3‐nonyl)adenine analogues

Abstract

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 i s thought to be essential for proper functioning of mammalian cells. ADA inhibitors may have several clinical applications (i.e., in the chemotherapy of lyrnphoproliferative disorders, in the immunosuppresive therapy, in adenosine level modulation). Modification of the purine moiety of adenosine led to ADA inhibitors. In particular, l-deazaadenosine (1, Ki = 0.66 pM) and its 2'-deoxy derivative (21, Ki = 0.19 JLM) 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 l-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-l-(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. o 1993 WiIey-Liss, Inc.

Adenosine deaminase: Functional implications and different classes of inhibitors

“…The last step consists in ammonia elimination but this pathway is not yet completely understood. 70 However, the exact role of the tryptophan residues in the catalytic mechanism of ADA still needs to be clearly elucidated. 66±68 Upon ultraviolet irradiation and chemical modi®cations of calf intestine ADA, the transformation of¯uorescent tryptophan residues occurs with the reduced enzymatic catalytical activity and con®rms the likely location of tryptophans near the binding site of the enzyme.…”

Facile Synthesis of Fluorinated Pyrrolo[2,3-b]pyridines

“…The practical synthetic route to pyrrolo[2, 3-b]pyridines, starting from the 5-amino-1-tert-butyl-1H-pyrrole-3-carbonitrile (8) and a number of 1,3-CCC-biselectrophiles containing a fluoroalkyl group (10,12,14).…”

Antiviral Properties of Deazaadenine Nucleoside Derivatives

“…In particular, deaza analogues of natural purine nucleosides have been thoroughly investigated from both the synthetic and the biological point of view. In fact, many papers have been published on the preparation of 1-deazapurine [6,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25], 3-deazapurine [6,20,[26][27][28][29][30][31][32], 7-deazapurine [6,[33][34][35][36][37][38][39][40][41], 1,3-dideazapurine [6,[42][43][44][45], 1,7-dideazapurine [46,47], and 3,7-dideazapurine [48][49][50][51][52] nucleosides.…”