4',1'a-Methanocarbocyclic Adenosine Analogues as Potential Inhibitors of S-Adenosylhomocysteine Hydrolase

Cyclopropane-fused carbocyclic adenosine ( 4 ) and its 5'carboxaldehyde analogue (5) were synthesized as potential inhibitors of Sadenosylhomocysteine hydrolase.The key bicyclo[3.1.0]hexanealcohol (8) was obtained from the optically pure cyclopentenone synthon (6), and attachment of the purine base was performed in a single step from the methylsulfonate ester of 8 (compound (9)).Both target compounds behaved as weak inhibitors of the hydrolase.S-Adenosylhomocysteine (AdoHcy) hydrolase catalyzes the interconversion of AdoHcy into adenosine and homocysteine and plays an important role in regulating S-adenosyl-L-methionine (AdoMet)-dependent methyl transferase activity.1It has been established that the accumulation of AdoHcy levels that result from AdoHcy hydrolase inhibition correlates well with the antiviral activity of these inhibitors, and hence, the development of more selective and powerful inhibitors of this enzyme continues to be an amactive goal for chemotherapeutic purposes.2.3 Neplanocin A (1) and aristeromycin (2) are the paradigm inhibitors of AdoHcy hydmlase.44Therefore, we decided to investigate the effects of fusing a cyclopropane ring at the site of the double bond in neplanocin A, which essentially transforms the molecule into an aristeromycin analogue (4) with a rigid carbasugar moiety possessing a North-type form or ring pucker,7.8as defined in the pseudorotational cycle.9Since both adenosine-5'-carboxaldehydelo and aristeromycin-5'carboxaldehyde (3)" are similarly HETEROCYCLES, Vd. 41, No. 12,1995