Design and synthesis of 4″,6″-unsaturated cyclic ADP-carbocyclic-ribose, a Ca<sup>2+</sup>-mobilizing agent selectively active in T cells
Kudoh T., Murayama T., Hashii M., Higashida H., Sakurai T., Maechling C., Spiess B., Weber K., Guse AH., Potter BVL., Arisawa M., Matsuda A., Shuto S.
We previously developed cyclic ADP-carbocyclic-ribose (cADPcR, 3a) as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca 2+ -mobilizing second messenger. The unsaturated carbocyclic-ribose analogs of cADPR, i.e., 4″,6″-didehydro-cADPcR (8a) and its inosine congener 4″,6″-didehydro-cIDPcR (8b) were newly designed and successfully synthesized using the key intramolecular condensation reaction with S-phenyl phosphorothioate-type substrates. The Ca 2+ -mobilizing potency of the compounds was examined in sea urchin egg homogenates, NG108-15 neuronal cells, and permeabilized Jurkat T-lymphocytes, which may indicate that 4″,6″-didehydro-cADPcR is the first cADPR analog selectively active in T cells. Acid-base behavior and conformation of 8a were also investigated and compared with those of cADPcR. © 2008 Elsevier Ltd. All rights reserved.