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Design and synthesis of 4″,6″-unsaturated cyclic ADP-carbocyclic-ribose, a Ca-mobilizing agent selectively active in T cells |
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| Authors: | Takashi Kudoh Minako Hashii Takashi Sakurai Bernard Spiess Andreas H. Guse Mitsuhiro Arisawa Satoshi Shuto |
| Affiliation: | a Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan b Department of Pharmacology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan c Department of Biophysical Genetics, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan d Institut Gilbert Laustriat, Département de Pharmacochimie de la Communication Cellulaire, UMR 7175, Faculté de Pharmacie, 74 route du Rhin, BP60024, F-67401 Illkirch, France e The Calcium Signalling Group, University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, Martinistrasse 52, 20246 Hamburg, Germany f Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK |
| Abstract: | We previously developed cyclic ADP-carbocyclic-ribose (cADPcR, 3a) as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger. The unsaturated carbocyclic-ribose analogs of cADPR, i.e., 4″,6″-didehydro-cADPcR (8a) and its inosine congener 4″,6″-didehydro-cIDPcR (8b) were newly designed and successfully synthesized using the key intramolecular condensation reaction with S-phenyl phosphorothioate-type substrates. The Ca2+-mobilizing potency of the compounds was examined in sea urchin egg homogenates, NG108-15 neuronal cells, and permeabilized Jurkat T-lymphocytes, which may indicate that 4″,6″-didehydro-cADPcR is the first cADPR analog selectively active in T cells. Acid-base behavior and conformation of 8a were also investigated and compared with those of cADPcR. |
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