Synthesis of novel apio carbocyclic nucleoside analogues as selective A3 adenosine receptor agonists

Abstract

On the basis of the biological activity of neplanocin A and apio-dideoxyadenosine (apio-ddA), novel apio-neplanocin A analogues 5a-d, combining the properties of two nucleosides, were stereoselectively synthesized. The apio moiety of the target nucleosides 5a-d was stereoselectively introduced 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 Grubbs catalyst in methylene chloride. The final nucleosides 5a-d were synthesized from the condensation of 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 common intermediate 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 against S-adenosylhomocysteine hydrolase (SAH) up to 100 μ, maybe due to the absence of the secondary hydroxyl 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) at the A3 adenosine receptor without any binding affinity at the A 1 and A2A adenosine receptors. In conclusion, we have first developed novel carbocyclic nucleosides with unnatural apio-carbasugars using stereoselective hydroxymethylation and RCM reaction and also discovered a new template of human A3 adenosine receptor agonist, which play a great role in developing new A3 adenosine receptor agonist as well as in identifying the binding site of the receptor. © 2005 American Chemical Society.