Design, Synthesis, and Chemical and Biological Properties of Cyclic ADP-4-Thioribose as a Stable Equivalent of Cyclic ADP-Ribose

Abstract

Here we describe the successful synthesis of cyclic ADP-4-thioribose (cADPtR, ), designed as a stable mimic of cyclic ADP-ribose (cADPR,), a Ca-mobilizing second messenger, in which the key N1-β-thioribosyladenosine structure was stereoselectively constructed by condensation between the imidazole nucleoside derivative and the 4-thioribosylamine via equilibrium in between the α-anomer () and the β-anomer () during the reaction course. cADPtR is, unlike cADPR, chemically and biologically stable, while it effectively mobilizes intracellular Ca like cADPR in various biological systems, such as sea urchin homogenate, NG108-15 neuronal cells, and Jurkat T-lymphocytes. Thus, cADPtR is a stable equivalent of cADPR, which can be useful as a biological tool for investigating cADPR-mediated Ca-mobilizing pathways.

Roles of NAD+ and Its Metabolites Regulated Calcium Channels in Cancer

“…has made brilliant contributions to the identification of these NAD + metabolites as these ion channels activators/regulators, which have been cited above. More importantly, based on the fact that these ion channels have been regarded as new cancer therapeutic targets, Professor Potter has designed and synthesized a series of ligands/inhibitors of these calcium channels [ 72 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 ], which certainly play critical roles in the development of anti-cancer drugs targeting these ion channels. In addition, some potassium and sodium channels can also be activated by NAD + and its metabolites, and there are also some calcium channels whose activity can be indirectly affected by NAD + and its metabolites.…”

25 Years of Collaboration with A Genius: Deciphering Adenine Nucleotide Ca2+ Mobilizing Second Messengers Together with Professor Barry Potter

“…Many of those were also tested in T cells, e.g., 2”-NH 2 -cADPR [ 23 ], cyclic aristeromycin diphosphoribose [ 24 ], and N 1-cyclic inosine diphosphoribose and 8-modified analogues thereof [ 25 , 26 , 27 , 28 , 29 ]. While the carbocyclic derivative of the northern ribose of cADPR was only characterized as a weak agonist in T cells [ 30 ], the thioribose analogue, cADP-4-thio-ribose (cADPtR), proved to be a full agonist [ 31 , 32 ]. A more comprehensive review of the structure–activity relationship of cADPR is shown in Figure 4 [ 33 ].…”