RESUMO
A novel trifluoromethylated analogue of cADPR, 8-CF3-cIDPDE (5) was designed and synthesized via construction of N1,N9-disubstituted hypoxanthine, trifluoromethylation and intramolecular condensation. A series of acyclic analogues of cADPR were also designed and synthesized. These compounds could be useful molecules for studying the structure-activity relationship of cADPR analogues and exploring the cADPR/RyR Ca2+ signalling system.
Assuntos
ADP-Ribose Cíclica/análogos & derivados , ADP-Ribose Cíclica/síntese química , Hidrocarbonetos Fluorados/síntese química , Sinalização do Cálcio , ADP-Ribose Cíclica/química , Hidrocarbonetos Fluorados/química , Hipoxantina/química , Canal de Liberação de Cálcio do Receptor de RianodinaRESUMO
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.