Design and synthesis of N6-substituted-4′-thioadenosine-5′-uronamides as potent and selective human A 3 adenosine receptor agonists

Abstract

On the basis of a bioisosteric rationale, 4′-thionucleoside analogues of IB-MECA ( N 6-(3-Iodo-benzyl)-9-(5′-methylaminocarbonyl-β- d-ribofuranosyl)adenine), which is a potent and selective A 3 adenosine receptor (AR) agonist, were synthesized from d-gulonic acid γ-lactone. The 4′-thio analogue ( 5h) of IB-MECA showed extremely high binding affinity ( K i = 0.25 nM) at the human A 3AR and was more potent than IB-MECA ( K i = 1.4 nM). Bulky substituents at the 5′-uronamide position, such as cyclohexyl and 2-methylbenzyl, in this series of 2-H nucleoside derivatives were tolerated in A 3AR binding, although small alkyl analogues were more potent.