Adenosine deaminase inhibitors. Synthesis and biological activity of deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine.
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.
Cristalli
G
G
Dipartimento di Scienze Chimiche, Università di Camerino, Italy.
Franchetti
P
P
Grifantini
M
M
Vittori
S
S
Lupidi
G
G
Riva
F
F
Bordoni
T
T
Geroni
C
C
Verini
M A
MA
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D009700:Nucleoside Deaminases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014740:Vidarabine / Q000494:pharmacology
D058892:Adenosine Deaminase Inhibitors; D000970:Antineoplastic Agents; D000998:Antiviral Agents; C054818:7-deaza-9-(2-hydroxy-3-nonyl)adenine; C054820:1,3-dideaza-9-(2-hydroxy-3-nonyl)adenine; C010192:9-(2-hydroxy-3-nonyl)adenine; C040554:(2R,3S)-3-(4-Amino-1H-imidazo(4,5-c)pyridin-1-yl)-2-nonanol; D009700:Nucleoside Deaminases; D014740:Vidarabine; D000225:Adenine