Adenosine deaminase inhibitors. Synthesis and biological activity of deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine.

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Cristalli G, Franchetti P, Grifantini M, Vittori S, Lupidi G, Riva F, Bordoni T, Geroni C, Verini MA

Adenosine deaminase inhibitors. Synthesis and biological activity of deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine.

J Med Chem. 1988 Feb;31(2):390-3.

PubMed ID

3339608 [ View in PubMed

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Abstract

Two new deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, 1), 7-deaza-EHNA (6) and 1,3-dideaza-EHNA (11), were synthesized and evaluated for adenosine deaminase (ADA) inhibitory activity and compared with EHNA, 1-deaza-EHNA (2), and 3-deaza-EHNA (3). Substitution of a methine group for a nitrogen atom in the 7-position of the purine moiety of EHNA produces a dramatic drop in the inhibitory activity (Ki = 4 X 10(-4) M) whereas compounds 2 and 3 are still good inhibitors (Ki = 1.2 X 10(-7) M and 6.3 X 10(-9) M respectively). EHNA and its deaza analogues so far synthesized were also tested in vitro for their antiviral and antitumor activity in a range of cellular systems. EHNA and 1-deaza-EHNA are equiactive as inhibitors of human respiratory syncytial virus (HRSV) replication (MIC = 6.25 micrograms/mL) while the other compounds are inactive. On the other hand, all the examined compounds displayed an antitumor activity comparable to that of the reference compound 1-beta-D-arabinofuranosyladenine (ara-A), 7-deaza-EHNA being the most active of all. The results obtained showed that there is no correlation between adenosine deaminase inhibition and antiviral or antitumor activity in this series of compounds. 3-Deaza-EHNA, the most active inhibitor of ADA among the EHNA deaza analogues, greatly potentiates the antitumor activity of ara-A in vitro. In vivo activity was observed only when the two compounds were used in combination.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Vidarabine	Adenosine deaminase	Protein	Humans	Unknown	Substrate	Details