Synthesis of 8-Substituted Analogues of Cyclic ADP-4-Thioribose and Their Unexpected Identification as Ca 2+ -Mobilizing Full Agonists

A series of 8-substituted analogues of cyclic ADP-4-thioribose (cADPtR, 3), which is a stable equivalent of Ca -mobilizing second messenger cyclic ADP-ribose (cADPR, 1), were designed as potential pharmacological tools for studies on cADPR-modulated Ca signaling pathways. These 8-amino analogue (8-N...

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Bibliographic Details
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 United States 13.07.2017
Subjects
Animals
Azides - chemistry
Azides - pharmacology
Calcium - metabolism
Calcium Signaling - drug effects
Cyclic ADP-Ribose - analogs & derivatives
Cyclic ADP-Ribose - chemistry
Cyclic ADP-Ribose - pharmacology
Halogenation
Models, Molecular
Sea Urchins - drug effects
Sea Urchins - metabolism
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Summary:A series of 8-substituted analogues of cyclic ADP-4-thioribose (cADPtR, 3), which is a stable equivalent of Ca -mobilizing second messenger cyclic ADP-ribose (cADPR, 1), were designed as potential pharmacological tools for studies on cADPR-modulated Ca signaling pathways. These 8-amino analogue (8-NH -cADPtR, 4), 8-azido analogue (8-N -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-NH -cADPR (2) is a well-known potent antagonist against cADPR-inducing Ca -release, the 4-thioribose congener 8-NH -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 Ca -signaling pathway, which can contribute to clarify the structure-agonist/antagonist activity relationship.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b00540