ADENOSINE-DEAMINASE INHIBITORS - SYNTHESIS AND BIOLOGICAL EVALUATION OF PUTATIVE METABOLITES OF (-ERYTHRO-9-(2S-HYDROXY-3R-NONYL)ADENINE())

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.