C. Vargeese et al., ADENOSINE-DEAMINASE INHIBITORS - SYNTHESIS AND BIOLOGICAL EVALUATION OF PUTATIVE METABOLITES OF (-ERYTHRO-9-(2S-HYDROXY-3R-NONYL)ADENINE()), Journal of medicinal chemistry, 37(22), 1994, pp. 3844-3849
The synthesis and biological evaluation of three chain-hydroxylated ()-erythro-9-(2S-hydroxy-3R-nonyl)adenine [(+)-EHNA] derivatives are re
ported. Hydroxy groups at positions 9', 8', and 8',9' (12, 25, and 16)
were introduced by either epoxidation or hydroboration of a terminal
olefinic intermediate. Affinities for calf intestinal adenosine deamin
ase (ADA) were determined from the steady-state inhibition of adenosin
e deamination. K-i values of 0.82, 3.8, 6.4, and 15.8 nM were estimate
d for (+)-EHNA, 9'-hydroxy-(+)-EHNA (12), 8'-hydroxy-(+)-EHNA (25), an
d 8',9'-dihydroxy-(+)-EHNA (16), respectively, by assuming a single cl
ass of binding sites. However, the data for all inhibitors conformed m
ore closely to the kinetics of a heterogeneous system with different a
ffinities for two or more binding sites. The fairly high potencies of
12 and 25 suggest that other substitutions at the terminal position of
the nonyl chain could yield useful ADA inhibitors.