Issue 20, 2010
From the journal:

Organic & Biomolecular Chemistry

Trifluoromethylated cyclic-ADP-ribose mimic: synthesis of 8-trifluoromethyl-N1-[(5′′-O-phosphorylethoxy)methyl]-5′-O-phosphorylinosine-5′,5′′-cyclic pyrophosphate (8-CF3-cIDPRE) and its calcium release activity in T cells†

Min Dong,‡a   Tanja Kirchberger,‡b   Xiangchen Huang,a   Zhen Jun Yang,a   Liang Ren Zhang,a   Andreas H. Guse*b  and  Li He Zhang*a  

* Corresponding authors

a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
E-mail: zdszlh@bjmu.edu.cn
Fax: +86-10-82802724
Tel: +86-10-82801700

b The Calcium Signaling Group, University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, Germany
E-mail: guse@uke.de
Fax: +49-40-7410-59880
Tel: +49-40-7410-52828

Abstract

A convenient trifluoromethylation method was firstly applied to the synthesis of 8- CF3-purine nucleosides. On the basis of this method, new protection and deprotection strategies were developed for the successful synthesis of the trifluoromethylated cyclic-ADP-ribose mimic, 8-CF3-cIDPRE 1. Using intact, fura-2-loaded Jurkat T cells compound 1 and 2′,3′-O-isopropylidene 8-CF3-cIDPRE 14 were characterized as membrane-permeant cADPR agonists. Contrary to the 8-substituted cADPR analogues that mainly act as antagonists of cADPR in cells, 8-substituted cIDPRE derivatives were shown to be Ca2+ mobilizing agonists. Here we report that even compound 1, the 8-substituted cIDPRE with the strong electron withdrawing CF3 group, behaves as an agonist in T cells. Interestingly, also the partially protected 2′,3′-O-isopropylidene 8-CF3-cIDPRE activated Ca2+ signaling indicating only a minor role for the hydroxyl groups of the southern ribose of cADPR for its biological activity. To our knowledge 8-CF3-cIDPRE 1 is the first reported fluoro substituted cADPR mimic and 8-CF3-cIDPRE 1 and compound 14 are promising molecular probes for elucidating the mode of action of cADPR.

Graphical abstract: Trifluoromethylated cyclic-ADP-ribose mimic: synthesis of 8-trifluoromethyl-N1-[(5′′-O-phosphorylethoxy)methyl]-5′-O-phosphorylinosine-5′,5′′-cyclic pyrophosphate (8-CF3-cIDPRE) and its calcium release activity in T cells

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Article information

DOI
https://doi.org/10.1039/C0OB00090F
Article type
Paper
Submitted
07 May 2010
Accepted
28 Jun 2010
First published
25 Aug 2010

Org. Biomol. Chem., 2010,8, 4705-4715

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Trifluoromethylated cyclic-ADP-ribose mimic: synthesis of 8-trifluoromethyl-N1-[(5′′-O-phosphorylethoxy)methyl]-5′-O-phosphorylinosine-5′,5′′-cyclic pyrophosphate (8-CF3-cIDPRE) and its calcium release activity in T cells

M. Dong, T. Kirchberger, X. Huang, Z. J. Yang, L. R. Zhang, A. H. Guse and L. H. Zhang, Org. Biomol. Chem., 2010, 8, 4705 DOI: 10.1039/C0OB00090F

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