title: Trifluoromethylated cyclic-ADP-ribose mimic: synthesis of 8-trifluoromethyl-N(1)-[(5''-O-phosphorylethoxy)methyl]-5'-O-phosphorylinosine-5',5''-cyclic pyrophosphate (8-CF(3)-cIDPRE) and its calcium release activity in T cells.
abstract: A convenient trifluoromethylation method was firstly applied to the synthesis of 8- CF(3)-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-CF(3)-cIDPRE 1. Using intact, fura-2-loaded Jurkat T cells compound 1 and 2',3'-O-isopropylidene 8-CF(3)-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 Ca(2+) mobilizing agonists. Here we report that even compound 1, the 8-substituted cIDPRE with the strong electron withdrawing CF(3) group, behaves as an agonist in T cells. Interestingly, also the partially protected 2',3'-O-isopropylidene 8-CF(3)-cIDPRE activated Ca(2+) signaling indicating only a minor role for the hydroxyl groups of the southern ribose of cADPR for its biological activity. To our knowledge 8-CF(3)-cIDPRE 1 is the first reported fluoro substituted cADPR mimic and 8-CF(3)-cIDPRE 1 and compound 14 are promising molecular probes for elucidating the mode of action of cADPR.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Min
authors.initials: M
authors.lastname: Dong
authors.forename: Tanja
authors.initials: T
authors.lastname: Kirchberger
authors.forename: Xiangchen
authors.initials: X
authors.lastname: Huang
authors.forename: Zhen Jun
authors.initials: ZJ
authors.lastname: Yang
authors.forename: Liang Ren
authors.initials: LR
authors.lastname: Zhang
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Guse
authors.forename: Li He
authors.initials: LH
authors.lastname: Zhang
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000737:chemistry; D002118:Calcium / Q000378:metabolism*; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D007291:Inosine Monophosphate / Q000031:analogs & derivatives / Q000737:chemistry; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: C555721:8-trifluoromethyl-N1-((5''-O-phosphorylethoxy)methyl)-5'-O-phosphorylinosine-5',5''-cyclic pyrophosphate; C494342:N(1)-((5''-O-phosphorylethoxy)methyl)-5'-O-phosphorylinosine 5',5''-cyclic pyrophosphate; D036563:Cyclic ADP-Ribose; D007291:Inosine Monophosphate; D000246:Adenosine Diphosphate Ribose; D002118:Calcium