Inhibition of Adenosine Deaminase From Several Sources by Deaza Derivatives of Adenosine and Ehna

Abstract

Deaza analogues of adenosine and EHNA were tested as inhibitors of the enzyme adenosine deaminase (ADA) obtained from several sources including human erythrocytes, calf intestine, Saccaromices cerevisiae, Escherichia coli and Takadiastase. Ki values of the inhibitors suggest differences among the enzymes both at purine and erythro-nonyl binding site. Among the ribofuranosyl derivatives, 1-deazaadenosine is the best inhibitor, its Ki ranging between 3.5 x 10(-7) and 4 x 10(-5) M for ADA from erythrocytes and Takadiastase respectively. Only ADA from erythrocytes and calf intestine bind EHNA and some of deazaEHNA analogues; 3-deazaEHNA behaves very similarly to EHNA both in affinity and slow binding mechanism, whereas 1-deazaEHNA, though less potent, is a good inhibitor.

Theoretical Study of the Structure of Adenosine Deaminase Complexes with Adenosine Analogues: I. Aza-, Deaza-, and Isomeric Azadeazaanalogues of Adenosine

“…The substrate and inhibitor properties of these compounds toward the mammalian ADA have already been described in literature [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] (Table 2). This group of compounds includes analogues prone to deamination with this enzyme [10, 12, 14, 16-18, 25, 26], the competitive enzyme inhibitors [11,13,[18][19][20][21]26], the nucleosides with no effect on the kinetics of adenosine deamination [13, 15, 19, 20, and 22-25], and the nucleosides whose substrate properties have not been studied [27][28][29][30][31][32][33][34][35][36][37][38].…”

“…This group of compounds includes analogues prone to deamination with this enzyme [10, 12, 14, 16-18, 25, 26], the competitive enzyme inhibitors [11,13,[18][19][20][21]26], the nucleosides with no effect on the kinetics of adenosine deamination [13, 15, 19, 20, and 22-25], and the nucleosides whose substrate properties have not been studied [27][28][29][30][31][32][33][34][35][36][37][38]. The available experimental information allows an analysis of the relationship between the structure and the substrate properties of the nucleoside analogues toward ADA.…”

Synthesis and Adenosine Deaminase Inhibitory Activity of 3′-Deoxy-1-deazaadenosines

“…± The new compounds 6, 7, and 11 ± 14 were evaluated as inhibitors of adenosine deaminase from calf intestine [22], and the results are listed in Table 2. The 2'-deoxy-1-deazaadenosine (16) and the corresponding 2-Cl derivative 15 were reported as reference compounds [14 ± 16].…”

“…Enzyme Assay. The method used for determination of the activity against ADA has been described in a preceding paper [22].…”

Inhibition studies on membrane adenosine deaminase from human placenta

“…Adenosine, 2'-deoxyadenosine, purine riboside, 2-chloropurin riboside, and 2-amino-6-methoxypurin riboside were purchased from Sigma Chemical Co. 2'-deoxycoformycin was kindly donated by Dr. Suffness of the cancer Institute of Bethesda. Other inhibitors used were synthetized in our laboratory (12). CH-Sepharose 4B, Sephacryl S-300, and Superose 12, Mono P were obtained from Pharmacia.…”