Abstract
Novel cADPR mimics, which integrate nucleobase, northern and southern ribose modifications were synthesized. The key steps of the synthesis were a Cu(I)-catalyzed Hüisgen [3+2] cycloaddition and a microwave-assisted intramolecular pyrophosphorylation. Preliminary biological investigations showed that these cADPR mimics are membrane-permeating agonists of the calcium signaling pathway. The introduction of chlorine or fluorine at the 2'-position of the southern riboses led to a decrease of activity. The existence of a hydrophobic group on the 3'-OH of the southern riboses does not obviously alter the agonistic activity.
Highlights
Cyclic adenosine disphosphate ribose is a universal Ca2+ mobilizing secondary messenger first identified in the sea urchin egg system [1]
The nucleobase of cADPR was simplified in our previous study; we have found that triazole-based cADPR analogues 3,4 are cell-permeating mild agonists of the cADPR/ryanodine receptor (RyR) calcium pathway [25]
This study shows that the agonistic activity is maintained in the case of disappearance of the 2'-OH, which emphasizes the importance of the structure of the nucleobase on the effect of the 2'-OH on calcium mobilization
Summary
Cyclic adenosine disphosphate ribose (cADPR, 1, Figure 1) is a universal Ca2+ mobilizing secondary messenger first identified in the sea urchin egg system [1]. The structures include modifications of the pyrophosphate [9,10,11,12], purine [13,14,15,16] and southern and northern riboses [17,18,19,20] of cADPR. These analogues can agonize or antagonize cADPR/RyR calcium signal pathway
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