Nucleosides and nucleotides. 103. 2-Alkynyladenosines: a novel class of selective adenosine A2 receptor agonists with potent antihypertensive effects

Abstract

The synthesis and receptor-binding activities at A1 and A2 adenosine receptors for a series of 2-alkynyladenosines are described. The palladium-catalyzed cross-coupling reaction of 2-iodoadenosine (4a) with various terminal alkynes in the presence of bis(triphenylphosphine)palladium dichloride and cuprous iodide in N,N-dimethylformamide containing triethylamine gives 2-alkynyladenosines (5a-r). An economical synthetic method for the preparation of 9-(2,3,5-tri-O-acetyl-1-beta-D-ribofuranosyl)-6-chloro-2-iodopurine++ + (2), which is a precursor of 4a, is also included. Several transformation reactions of 2-(1-octyn-1-yl)adenosine (5e) and 2-(1-ethyn-1-yl)adenosine (9) and a similar cross-coupling reaction of 6-chloropurine derivative 11 and 8-bromoadenosine (13) with 1-octyne are also reported. Many of these 2-alkynyladenosines tested for A1 and A2 adenosine receptor binding activities in rat brain are selective for the A2 adenosine receptor. Among them, 2-(1-hexyn-1-yl)adenosine (5c) has the highest affinity for both A1 and A2 receptors with Ki values of 126.5 and 2.8 nM, respectively. The structure-activity relationship of this series of compounds including 6- or 8-alkynylpurine nucleosides and 2-alkyl- and 2-alkenyladenosines is discussed in terms of potency at both receptor subtypes. Additionally, we describe how hypotensive activity and heart rate decrease brought on by 5 and some other compounds with spontaneously hypertensive rats are proportional to the order of the potency to both A1 and A2 binding affinities. Thus, 2-alkynyladenosines are interesting and promising as antihypertensive agents that should be considered for further detailed preclinical evaluation.

2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors

“…A number of substitutions at the 2-position, which were previously found to contribute to the affinity for the rat A 2A AR [20,28,29], were also demonstrated to be important for the affinity and selectivity at the human A 2A AR homologue. A single substitution at the 2-position might contribute significantly to both A 2A AR affinity and selectivity.…”

“…chloro, methylthio, and alkynyl groups). The SAR of alkynyl groups at the 2-position based on affinity at several subtypes of ARs has been explored [21,29].…”

Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design

“…31 Trifluoroacetylation of the C2′ amine and acetylation of the C3′ and C5′ hydroxyls to yield 2′-deoxy-2′-trifluoroacetamidoinosine (3) and 2′-deoxy-2′-trifluoroacetamido-3′,5′-O-(diacetyl)-inosine (4), respectively, is accomplished in greater than 95% yield for each step. By use of the methodology of Matsuda et al, 32 subsequent chlorination of the C6 position of 4 with phosphorus oxychloride to yield 9-[2′-deoxy-2′-trifluoroacetamido-3′,5′-O-(diacetyl)]-(1-β-D-ribofuranosyl)-6-chloropurine (5) is accomplished in better than 90% yield. Starting from the commercially available arabinose adenosine and transforming through nine steps, the intermediate 5 can be synthesized in 65% overall yield.…”

Synthesis of 6-Alkoxyl-2-propylthio-8-azapurine Nucleosides and Their Antiplatelet Aggregation Activity Evaluation

“…[5～7] 、抗肿瘤 [8] 和治疗血栓性疾 病方面 [9,10] 都有着良好的医药活性. 近年来, 阿斯利康 公司通过对 8-氮杂嘌呤核苷核糖环的 5'-位进行官能团 修饰, 以及对嘌呤环 2,6-位进行烷硫基或烷氨基取代, 合成了一系列 8-氮杂嘌呤核苷化合物, 并对这些化合物 进 行 了 抗 血 小 板 聚 集 的 筛 选 [11,12] .…”