A series of 8-substituted analogues of cyclic ADP-4-thioribose (cADPtR, 3), which is a stable equivalent of Ca²⁺-mobilizing second messenger cyclic ADP-ribose (cADPR, 1), were designed as potential pharmacological tools for studies on cADPR-modulated Ca²⁺ signaling pathways. These 8-amino analogue (8-NH₂-cADPtR, 4), 8-azido analogue (8-N₃-cADPtR, 5), and 8-chloro analogue (8-Cl-cADPtR, 6) were efficiently synthesized, where the stereoselective N1-β-thioribosyladenine ring closure reaction via an α/β-equilibrium of the 1-aminothioribose derivative and construction of the characteristic 18-membered pyrophosphate ring by Ag⁺-promoted activation of a phenyl phosphorothioate type substrate were the two key steps. Although 8-NH₂-cADPR (2) is a well-known potent antagonist against cADPR-inducing Ca²⁺-release, the 4-thioribose congener 8-NH₂-cADPtR turned out unexpectedly to be a full agonist in sea urchin egg homogenate evaluation system. This important finding suggested that the ring-oxygen in the N1-ribose of cADPR analogues is essential for the antagonistic activity in the Ca²⁺-signaling pathway, which can contribute to clarify the structure–agonist/antagonist activity relationship.

中文翻译：

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环状ADP-4-硫代核糖的8-取代类似物的合成及其作为Ca ²⁺活化的全激动剂的意外鉴定。

设计了一系列稳定的等价于Ca ^2+的第二信使环状ADP-核糖（cADPR，1）的一系列环状ADP-4-硫代核糖（cADPtR，3）的8-取代类似物作为潜在的药理学工具cADPR调节的Ca ²⁺信号通路的研究。这些8-氨基类似物（8-NH ₂ -cADPtR，4），8-叠氮基类似物（8-N ₃ -cADPtR，5）和8-氯类似物（8-Cl-cADPtR，6）被有效地合成，其中立体选择性N通过1-氨基硫代核糖衍生物的α/β-平衡进行1-β-硫代核糖基腺嘌呤闭环反应和通过Ag ⁺促进苯基硫代磷酸酯型底物的活化来构建特征性的18元焦磷酸盐环是两个关键步骤。尽管8-NH ₂ -cADPR（2）是众所周知的针对诱导cADPR的Ca ²⁺释放的有效拮抗剂，但是4-硫代核糖同源物8-NH ₂ -cADPtR出人意料地是海胆卵中的一种完全激动剂。匀浆评价系统。这一重要发现表明，cADPR类似物的N 1-核糖中的环氧对于Ca ^2+中的拮抗活性至关重要。-信号通路，可以有助于阐明结构-激动剂/拮抗剂活性之间的关系。