| Abstract
| - On the basis of the biological activity of neplanocin A and apio-dideoxyadenosine (apio-ddA), novelapio-neplanocin A analogues 5a−d, combining the properties of two nucleosides, were stereoselectively synthesized. The apio moiety of the target nucleosides 5a−d was stereoselectivelyintroduced by treating lactol 10 with 37% formaldehyde in the presence of potassium carbonate.The carbasugar moiety of neplanocin A was successively built by exposing diene 12 on a Grubbscatalyst in methylene chloride. The final nucleosides 5a−d were synthesized from the condensationof the glycosyl donor 14 with nucleic bases under the standard Mitsunobu conditions. Similarly,apio-aristeromycin 6 and (N)-apio-methanocarbaadenosine 7 were derived from the commonintermediate 13 using catalytic hydrogenation and Simmons−Smith cyclopropanation as key steps.All of the final nucleosides 5a−d, 6, and 7 did not show significant inhibitory activity againstS-adenosylhomocysteine hydrolase (SAH) up to 100 μM, maybe due to the absence of the secondaryhydroxyl group at the C3‘-position, which should be oxidized by cofactor-bound NAD+. However,apio-neplanocin A (5a) showed potent and highly selective binding affinity (Ki = 628 ± 69 nM) atthe A3 adenosine receptor without any binding affinity at the A1 and A2A adenosine receptors. Inconclusion, we have first developed novel carbocyclic nucleosides with unnatural apio-carbasugarsusing stereoselective hydroxymethylation and RCM reaction and also discovered a new templateof human A3 adenosine receptor agonist, which play a great role in developing new A3 adenosinereceptor agonist as well as in identifying the binding site of the receptor.
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