Synthesis and agonist activity of cyclic ADP-ribose analogues with substitution of the northern ribose by ether or alkane chains.
Novel analogues of cADPR with adenine as base and ether (10a) or different alkane chain (10b-d) substitutions of the northern ribose were synthesized from protected imidazole nucleoside 1 in good yields. The pharmacological activities of cyclic inosine diphosphoribose ether (cIDPRE) and the compounds (10a-d) were analyzed in intact human Jurkat T-lymphocytes. The results indicate that the analogues 10a-d permeate the plasma membrane and are weak agonists of the cADPR/ryanodine receptor signaling system in intact human Jurkat T cells. They are the first membrane-permeant and biologically active cADPR analogues that contain ether or alkane bridges instead of the northern ribose and retain adenine as its base.
Xu
Jianfeng
J
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
Yang
Zhenjun
Z
Dammermann
Werner
W
Zhang
Liangren
L
Guse
Andreas H
AH
Zhang
Li-He
LH
D000225:Adenine / Q000737:chemistry; D000473:Alkanes / Q000737:chemistry*; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004987:Ethers / Q000737:chemistry*; D006801:Humans; D019169:Jurkat Cells; D011956:Receptors, Cell Surface / Q000819:agonists*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000473:Alkanes; D004987:Ethers; D011956:Receptors, Cell Surface; D019837:Ryanodine Receptor Calcium Release Channel; C067025:cyclic ADP-ribose receptor; D036563:Cyclic ADP-Ribose; D000225:Adenine; D002118:Calcium