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Pure Appl. Chem., 2008, Vol. 80, No. 8, pp. 1821-1825

Adenine-based calcium signal pathway messengers: Synthesis and agonistic properties of cyclic ADP-ribose analogs

Liangren Zhang1, Zhenjun Yang1, Andreas H. Guse2 and Lihe Zhang1

1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China
2 University Hospital Hamburg-Eppendorf, Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, Martinistr. 52, 20246 Hamburg, Germany

Abstract: A series of cyclic ADP-ribose (cADPR) analogs, in which modifications mainly focused on riboses, was synthesized in order to explore the molecular mechanism of calcium release regulated by cADPR. Biological activities investigated in intact T-lymphocytes showed that the structurally simplified analogs, N1-ethoxymethyl-substituted cyclic inosine diphosphoribose (cIDPRE), N1,N9-diethoxymethyl-substituted cyclic inosine diphosphoribose (cIDPDE), and N1-ethoxymethyl-substituted cyclic adenosine diphosphoribose (cADPRE) in which the northern ribose or both northern and southern riboses were replaced by ether linkages are membrane-permeant and induce calcium release from intracellular stores. This research has provided novel molecules to probe cADPR-mediated calcium signaling and enlarges our knowledge of the structure-activity relationships of cADPR analogs.