Synthesis and biological activity of 2-alkylated deoxyadenosine bisphosphate derivatives as P2Y 1 receptor antagonists

Abstract

A previous study around adenine nucleotides afforded the reference N 6-methyl-2′-deoxyadenosine-3′,5′-bisphosphate ( 1a, MRS 2179) as a selective human P2Y 1 receptor antagonist (p A 2=6.55±0.05) with antithrombotic properties. In the present paper, we have synthesized and tested in vitro various 2-substituted derivatives with the goal of exploring the 2-position binding region and developing more potent P2Y 1 receptor antagonists. Thus, we have adopted a novel and versatile chemical pathway using a palladium-catalyzed cross-coupling reaction with the 2-iodinated derivative 7 as a common intermediate for a very efficient synthesis of the 2-alkyl- N 6-methyl-2′-deoxyadenosine-3′,5′-bisphosphate nucleotides 1e– i. The biological activity was evaluated through the ability of compounds to inhibit ADP-induced platelet aggregation, intracellular calcium rise and to displace the specific binding of [ 33P]2-MeSADP. 2-Ethyl and 2-propyl groups appeared to be tolerated, whereas a bulky group or a C 3 linear substituent dramatically decreased potency of antagonists. The 2-ethynyl derivative 1h (p A 2=7.54±0.10) was significantly more potent (10-fold) as an antagonist when compared to the reference 1a, revealing a potential electronic interaction highly favorable between triple bond orbitals and the P2Y 1 receptor at this position.