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 antiχCN glycosyl torsion angle, their riboses have 3 distinct puckers (C2′-exo, C2′-endo and C1′-exo). In contrast, the a-X structure adopts a synχCN glycosyl torsion angle, which is stabilized by an intramolecular hydrogen bond between the N3 or purine base and the O5′ of the ribose (in C2′-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.
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