Takayoshi Tsuzuki1, Satoshi Takano1, Natsumi Sakaguchi1, Takashi Kudoh1, Takashi Murayama2, Takashi Sakurai2, Minako Hashii3, Haruhiro Higashida3, Karin Weber4, Andreas H Guse4, Tomoshi Kameda5, Takatsugu Hirokawa5, Yasuhiro Kumaki6, Mitsuhiro Arisawa1, Barry V L Potter7, Satoshi Shuto8. 1. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. 2. Department of Pharmacology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. 3. Department of Biophysical Genetics, Takaramachi, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan. 4. The Calcium Signalling Group, University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Department of Biochemistry and Signal Transduction, Martinistr. 52, 20246 Hamburg, Germany. 5. Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology, Aomi, Koutou-ku, Tokyo 135-0064, Japan. 6. Faculty of Sciences, Hokkaido University, Kita-11, Nishi-8, Kita-ku, Sapporo 060-0812, Japan. 7. Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK. 8. 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.
Abstract
Here we describe the successful synthesis of cyclic ADP-4-thioribose (cADPtR, 3), designed as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger, in which the key N1-β-thioribosyladenosine structure was stereoselectively constructed by condensation between the imidazole nucleoside derivative 8 and the 4-thioribosylamine 7 via equilibrium in 7 between the α-anomer (7α) and the β-anomer (7β) during the reaction course. cADPtR is, unlike cADPR, chemically and biologically stable, while it effectively mobilizes intracellular Ca2+ 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 Ca2+-mobilizing pathways.
Here we describe the successful synthesis of cyclic ADP-4-thioribose (cADPtR, 3), designed as a stable mimic of n class="Chemical">cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger, in which the key N1-β-thioribosyladenosine structure was stereoselectively constructed by condensation between the imidazole nucleoside derivative 8 and the 4-thioribosylamine 7 via equilibrium in 7 between the α-anomer (7α) and the β-anomer (7β) during the reaction course. cADPtR is, unlike cADPR, chemically and biologically stable, while it effectively mobilizes intracellular Ca2+ 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 Ca2+-mobilizing pathways.