Abstract
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.
Highlights
Cyclic adenosine diphosphate ribose, isolated from sea urchin eggs [1], is a metabolite of β-nicotinamide adenine dinucleotide (NAD+)
A series of cADPR analogues in which the southern and/or northern ribose was replaced by an ether chain were synthesized [6,7]
−63.358 ppm was observed in the 19F-NMR spectrum. These data strongly support the incorporation of the trifluoromethyl group
Summary
Cyclic adenosine diphosphate ribose (cADPR, 1, Figure 1), isolated from sea urchin eggs [1], is a metabolite of β-nicotinamide adenine dinucleotide (NAD+). A series of cADPR analogues in which the southern and/or northern ribose was replaced by an ether chain were synthesized [6,7] Most of those compounds, such as cIDPRE (2). Since the trifluoromethyl group imparts a variety of special physical and chemical properties to molecules, a number of trifluoromethylated compounds exhibit enhanced biological activity [8] Taking these points into account, we synthesized 8-CF3-cIDPRE (4, Figure 2). We found that this compound was a membrane permeate calcium agonist in Jurkat T cells [9]. The trifluoromethyl group is introduced to cIDPDE (8-CF3-cIDPDE, 5, Figure 2) This compound provides a complementary agent for understanding the effect of 8-substitution on calcium signalling property. To further explore the Ca2+-modulating activities of this novel class of cADPR mimics and their mechanism further, we have designed and synthesized acyclic analogues of cIDPRE and the trifluoromethylated analogues 6-8 (Figure 2)
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