Synthesis of Novel Apio Carbocyclic Nucleoside Analogues as Selective A_(3) Adenosine Receptor Agonists

다국어 초록 (Multilingual 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-4, 6, and 7 did not show significant inhibitory activity against S-adenosylllolllocysteine hydrolase (SAH) up to 100 ㎛, maybe due to the absence of the secondary hydroxyl group at tile C3'-position, which should be oxidized by cofactor-bound NAD^(+). However, aplo-neplanocin A (5a) showed potent and highly selective binding affinity (K_(i), = 628 ± 69 nM) at the A_(3) adenosine receptor without any binding affinity at the A_(1) and A_(2A) adenosine receptors. In conclusion, we have first developed novel carbocyclic nucleosides with unnatural apio-carbasugarsusing stereoselective hydroxymethylation and RCM reaction and also discovered a new template of human A_(3) adenosine receptor agonist, which play a great rote in developing new A_(3) adenosine receptor agonist as well as in identifying the binding site of the receptor.