Design, Synthesis, and Identification of 4″α-Azidoethyl-cyclic ADP-Carbocyclic-ribose as a Highly Potent Analogue of Cyclic ADP-Ribose, a Ca(2+)-Mobilizing Second Messenger

• Published in: Journal of medicinal chemistry Vol. 59; no. 15; pp. 7282 - 7286
• Main Authors: Sato, Takatoshi, Watanabe, Mizuki, Tsuzuki, Takayoshi, Takano, Satoshi, Murayama, Takashi, Sakurai, Takashi, Kameda, Tomoshi, Fukuda, Hayato, Arisawa, Mitsuhiro, Shuto, Satoshi
• Format: Journal Article
• Language: English
• Published: United States 11.08.2016
• Subjects: Calcium - metabolism; Calcium Signaling - drug effects; Cyclic ADP-Ribose - analogs & derivatives; Cyclic ADP-Ribose - chemical synthesis; Cyclic ADP-Ribose - chemistry; Cyclic ADP-Ribose - pharmacology; Drug Design; Molecular Conformation; Second Messenger Systems - drug effects
• ISSN: 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00437

Cyclic adenosine diphosphate-carbocyclic-ribose (cADPcR, 2) is a stable equivalent of cyclic adenosine diphosphate-ribose (cADPR, 1), a Ca(2+)-mobilizing second messenger. On the basis of the structure-activity relationship of cADPR-related compounds and three-dimensional structural modeling of cADPcR, we designed and synthesized cyclic-ADP-4″α-azidoethyl carbocyclic-ribose (N3-cADPcR, 3) to demonstrate that it has a highly potent Ca(2+)-mobilizing activity (EC50 = 24 nM). N3-cADPcR will be a useful precursor for the preparation of biological tools effective to investigate cADPR-mediated signaling pathways.