Synthesis of 8‑Substituted Analogues of Cyclic ADP-4-Thioribose and Their Unexpected Identification as Ca2+-Mobilizing Full Agonists

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 (...

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Published inJournal of medicinal chemistry Vol. 60; no. 13; pp. 5868 - 5875
Main Authors Takano, Satoshi, Tsuzuki, Takayoshi, Murayama, Takashi, Kameda, Tomoshi, Kumaki, Yasuhiro, Sakurai, Takashi, Fukuda, Hayato, Watanabe, Mizuki, Arisawa, Mitsuhiro, Shuto, Satoshi
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 13.07.2017
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
2ND-MESSENGER
ADP-CARBOCYCLIC-RIBOSE
NORTHERN RIBOSE
DESIGN
PHARMACOLOGY
CALCIUM-RELEASE
HYDROLYSIS
CHEMICAL-SYNTHESIS
DERIVATIVES
CYCLIZATION
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Summary: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.
Bibliography:KAKEN
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ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b00540