title: Synthesis of novel apio carbocyclic nucleoside analogues as selective a(3) 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 muM, 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 (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-carbasugars using stereoselective hydroxymethylation and RCM reaction and also discovered a new template of human A(3) adenosine receptor agonist, which play a great role in developing new A(3) adenosine receptor agonist as well as in identifying the binding site of the receptor.
authors.affiliation: Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Jeong A
authors.initials: JA
authors.lastname: Lee
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.forename: Hea Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: Kyung Ran
authors.initials: KR
authors.lastname: Kim
authors.forename: Kang Man
authors.initials: KM
authors.lastname: Lee
authors.forename: Bum Tae
authors.initials: BT
authors.lastname: Kim
authors.forename: Ki Jun
authors.initials: KJ
authors.lastname: Hwang
authors.forename: Moon Woo
authors.initials: MW
authors.lastname: Chun
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D058909:Adenosine A3 Receptor Agonists; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors*; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D018047:Receptors, Purinergic P1
chemical_list: D058909:Adenosine A3 Receptor Agonists; D004791:Enzyme Inhibitors; D018047:Receptors, Purinergic P1; C031096:neplanocin A; D043383:Adenosylhomocysteinase; D000241:Adenosine