Unusual conformational flexibility in N¹-substituted uncommon purine nucleosides Crystal structure of 1-allyl-isoguanosine and 1-allyl-xanthosine

Several new N¹-substituted uncommon purine nucleosides, including doridosine (1-methyl-isoguanosine; m-iG), 1-allyl-isoguanosine (a-iG) and 1-allyl-xanthosine (a-X), have been synthesized and tested as agonists for the adenosine receptors. Some have smooth muscle relaxant or negative chronotropic activities. The X-ray crystal structure of these compounds has been determined at atomic resolution in order to understand the structure-activity relationship. The structures were solved by direct methods and refined by full-matrix least-squares refinement procedure. The crystallographic parameters are: a-iG, space group P2₁, a=10.573 (1) Å, b=21.955 (2) Å, c=14.360 (1) Å, β=110.65 (1)°, no. of 3σ Fo's=4585, R=0.047; a-X, space group P2₁2₁2₁, a=16.015 (2) Å, b=16.239 (1) Å, c=5.3723 (5) Å, no. of 3σ Fo's= 1169, R=0.031. In the a-iG crystal, there are 4 independent molecules (with different conformation) per asymmetric unit. While all 4 molecules adopt anti_χCN glycosyl torsion angle, their riboses have 3 distinct puckers (C^2′-exo, C^2′-endo and C^1′-exo). In contrast, the a-X structure adopts a syn_χCN glycosyl torsion angle, which is stabilized by an intramolecular hydrogen bond between the N³ or purine base and the O^5′ of the ribose (in C^2′-endo pucker). Both purine bases (a-iG and a-X) are mainly in the keto tautomer form. For the isoguanine base, the averaged N¹C² bond distance (1.42 Å) is significantly longer than that (1.375 Å) of the guanine base. For the xanthine base, N³ nitrogen has an imino proton attached which is unambiguously located in the electron density map. The surprising flexibility in the ribose ring of these N¹-substituted uncommon purine nucleosides suggests flat the ribose moiety may not participate in the binding of nucleoside to the adenosine receptors.