Aristeromycin-5‘-carboxaldehyde:  A Potent Inhibitor of S-Adenosyl- l-homocysteine Hydrolase

In an earlier study, Liu et al. (Bioorg. Med. Chem. Lett. 1992, 2, 1741−1744) showed that both the E and Z isomers of 4‘,5‘-didehydro-5‘-fluoroaristeromycin were very potent irreversible inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase. However, it was unclear from a mechanistic standpoint whether these vinyl fluorides were themselves type-I mechanism-based inhibitors causing reduction of enzyme-bound NAD+ or whether they were prodrug for aristeromycin-5‘-carboxaldehyde, which was the ultimate type-I inhibitor. To elucidate this mechanism of enzyme inhibition, (4‘S)- and (4‘R)-aristeromycin-5‘-carboxaldehydes (1a,b) were synthesized in this study and shown to be potent type-I mechanism-based inhibitors of AdoHcy hydrolase with k 2/K i values of 4.4 × 106 and 8.2 × 104 M-1 min-1, respectively. However, Using 19F NMR and HPLC, it was shown that (4‘S)-4‘,5‘-didehydro-5‘-fluoroaristeromycin in the presence of AdoHcy hydrolase did not release fluoride ion or generate aristeromycin-5‘-carboxaldehyde (1a,b). These results suggest that the E and Z isomers of 4‘,5‘-didehydro-5‘-fluoroaristeromycin are inactivating AdoHcy hydrolase by directly reducing NAD+ to NADH and not using the hydrolytic activity of the enzyme to generate aristeromycin-5‘-carboxaldehyde.