Calcium‐Mobilizing Behaviors of Neutral Cyclic ADP‐Ribose Mimics that Integrate Modifications to the Nucleobase, Northern Ribose and Pyrophosphate. (22nd May 2018)

• Record Type: Journal Article
• Authors: Wang, Xuan; Zhang, Xiaoyan; Zhang, Kehui; Hu, Jianxing; Liu, Zhenming; Jin, Hongwei; Zhang, Liangren; Zhang, Lihe
• Is Part Of: Chembiochem. Volume 19:Number 13(2018)
• Page Start: 1444
• Page End: 1451
• Publication Date: 2018-05-22
• Subjects: cADPR mimics -- nucleotides -- ryanodine receptors -- signal transduction -- structure–activity relationships; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201800133
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Cyclic adenosine diphosphate ribose (cADPR) is an endogenous Ca 2+ mobilizer involved in diverse cellular processes. Mimics of cADPR play a crucial role in investigating the molecular mechanism(s) of cADPR‐mediated signaling. Here, compound3, a mimic of cADPR in which a neutral triazole moiety and an ether linkage were introduced to substitute the pyrophosphate and "northern" ribose components, respectively, was synthesized for the first time. The pharmacological activities in Jurkat cells indicated that this mimic is capable of penetrating plasma membrane and inciting Ca 2+ release from the endoplasmic reticulum (ER) through the action of ryanodine receptors (RyRs) and triggering Ca 2+ influx. Furthermore, a uridine moiety was introduced in place of adenine and the new cADPR mimics4 and5 were synthesized. The results of biological investigation showed that these mimics also targeted RyRs and retained moderate Ca 2+ agonistic activities. The results indicated that the neutral cADPR mimics had the same targets for inducing Ca 2+ signaling. Abstract : Ca 2+ signaling pathways : Cyclic ADP‐ribose (cADPR) mimics play a crucial role in investigating the molecular mechanism(s) of cADPR‐mediated calcium signaling, and some have been synthesized here. Neutral triazole, ether, and uridine systems (introduced as substitutes for pyrophosphate, "northern" ribose, and nucleobase, respectively) appear to activate Ca 2+ release in a similar way to cADPR.