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Article Abstract
Here we describe the successful synthesis of cyclic ADP-4-thioribose (cADPtR, ), designed as a stable mimic of cyclic ADP-ribose (cADPR, ), a Ca-mobilizing second messenger, in which the key N1-β-thioribosyladenosine structure was stereoselectively constructed by condensation between the imidazole nucleoside derivative and the 4-thioribosylamine via equilibrium in between the α-anomer () and the β-anomer () during the reaction course. cADPtR is, unlike cADPR, chemically and biologically stable, while it effectively mobilizes intracellular Ca like cADPR in various biological systems, such as sea urchin homogenate, NG108-15 neuronal cells, and Jurkat T-lymphocytes. Thus, cADPtR is a stable equivalent of cADPR, which can be useful as a biological tool for investigating cADPR-mediated Ca-mobilizing pathways.
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| http://dx.doi.org/10.1166/msr.2014.1035 | DOI Listing |
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Synthesis of 8-Substituted Analogues of Cyclic ADP-4-Thioribose and Their Unexpected Identification as Ca-Mobilizing Full Agonists.
J Med Chem
July 2017
Department of Pharmacology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
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.
View Article and Find Full Text PDFDesign, Synthesis, and Chemical and Biological Properties of Cyclic ADP-4-Thioribose as a Stable Equivalent of Cyclic ADP-Ribose.
Messenger (Los Angel)
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Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Here we describe the successful synthesis of cyclic ADP-4-thioribose (cADPtR, ), designed as a stable mimic of cyclic ADP-ribose (cADPR, ), a Ca-mobilizing second messenger, in which the key N1-β-thioribosyladenosine structure was stereoselectively constructed by condensation between the imidazole nucleoside derivative and the 4-thioribosylamine via equilibrium in between the α-anomer () and the β-anomer () during the reaction course. cADPtR is, unlike cADPR, chemically and biologically stable, while it effectively mobilizes intracellular Ca like cADPR in various biological systems, such as sea urchin homogenate, NG108-15 neuronal cells, and Jurkat T-lymphocytes. Thus, cADPtR is a stable equivalent of cADPR, which can be useful as a biological tool for investigating cADPR-mediated Ca-mobilizing pathways.
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Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan.