Syntheses and Calcium-Mobilizing Evaluations of <i>N</i>-Glycosyl-Substituted Stable Mimics of Cyclic ADP-Ribose

Huang, Lijun; Zhao, Yiyang; Yuan, Lan; Min, Ji-Mei; Zhang, Lihe

doi:10.1021/jm010530l

Cited by 34 publications

(40 citation statements)

References 32 publications

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“…Full synthetic details and full pharmacological characterization of cIDPRE will be published elsewhere. cIDPRE was synthesized from N-1-acetoxyethoxymethyl-substituted inosine using the similar seven steps described for the synthesis of N-1-glycosylsubstituted cyclic IDP-ribose derivatives (Huang et al, 2002a;Huang et al, 2002b). The synthetic compound was identified by 1 H and 31 P nuclear magnetic resonance (NMR) spectroscopy and mass spectroscopy after purification twice by high-performance liquid chromatography (HPLC).…”

Section: Synthesis Of N-1-ethoxymethyl-substituted Cyclic Inosine Dipmentioning

confidence: 99%

Amplification and propagation of pacemaker Ca2+ signals by cyclic ADP-ribose and the type 3 ryanodine receptor in T cells

Kunerth

Langhorst

Schwarzmann

et al. 2004

Journal of Cell Science

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Ligation of the T-cell receptor/CD3 complex results in global Ca2+ signals that are essential for T-cell activation. We have recently reported that these global Ca2+ signals are preceded by localized pacemaker Ca2+ signals. Here, we demonstrate for the first time for human T cells that an increase in signal frequency of subcellular pacemaker Ca2+ signals at sites close to the plasma membrane, in the cytosol and in the nucleus depends on the type 3 ryanodine receptor (RyR) and its modulation by cyclic ADP-ribose. The spatial distribution of D-myo-inositol 1,4,5-trisphosphate receptors and RyRs indicates a concerted action of both of these receptors/Ca2+ channels in the generation of initial pacemaker signals localized close to the plasma membrane. Inhibition or knockdown of RyRs resulted in significant decreases in (1) the frequency of initial pacemaker signals localized close to the plasma membrane, and (2) the frequency of localized pacemaker Ca2+ signals in the inner cytosol. Moreover, upon microinjection of cyclic ADP-ribose or upon extracellular addition of its novel membrane-permeant mimic N-1-ethoxymethyl-substituted cyclic inosine diphosphoribose, similarly decreased Ca2+ signals were observed in both type 3 RyR-knockdown cells and in control cells microinjected with the RyR antagonist Ruthenium Red. Taken together, our results show that, under physiological conditions in human T cells, RyRs play crucial roles in the local amplification and the spatiotemporal development of subcellular Ca2+ pacemaker signals.

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Section: Synthesis Of N-1-ethoxymethyl-substituted Cyclic Inosine Dipmentioning

confidence: 99%

Amplification and propagation of pacemaker Ca2+ signals by cyclic ADP-ribose and the type 3 ryanodine receptor in T cells

Kunerth

Langhorst

Schwarzmann

et al. 2004

Journal of Cell Science

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“…In recent years, on the other hand, methods for the chemical synthesis of cADPR analogs have been extensively studied, and useful cADPR analogs, which could not be prepared by the enzymatic and chemo-enzymatic methods, have been synthesized [10,[29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46]. In this review, we will mainly focus on these chemical synthetic studies of cADPR analogs.…”

Section: Introductionmentioning

confidence: 99%

Chemistry of Cyclic ADP-Ribose and its Analogs

Shuto¹,

Matsuda

2004

CMC

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Cyclic ADP-ribose (cADPR), a general mediator involved in Ca2+ signaling, has the characteristic 18-membered ring consisting of an adenine, two riboses and a pyrophosphate, in which the two primary hydroxyl groups of the riboses are linked by a pyrophosphate unit. This review focuses on the chemical synthetic studies of cADPR analogs. These analogs have been used quite effectively in proving the mechanism of cADPR-mediated Ca2+ signaling pathways. These analogs are also expected to be lead structures for the development of drugs. Although cADPR analogs can be synthesized by enzymatic and chemo-enzymatic methods using ADP-ribosyl cyclase, the analogs obtained by these methods are limited due to the substrate-specificity of the enzymes. Consequently, chemical synthetic methods providing a greater variety of cADPR analogs are required. Chemical synthetic studies have demonstrated that the construction of the large 18-membered ring structure is quite difficult. Another problem encountered in the synthesis is the construction of the N1-substituted purine nucleoside structure. The N1-substituted inosine derivatives were prepared by condensation between the N1-(2,4-dinitrophenyl)inosine derivatives and the appropriate amines. For the preparation of the N1-substituted adenosine structures, condensation of the 4-cyano-5-(alkoxymethyleneamino)imidazole nucleosides with the appropriate amines was found to be effective. The first chemical construction of the 18-membered ring was achieved using a bisphosphate-type substrate conformationally restricted in the cyclized product-like syn-form around the N9-glycosyl linkage; however, the yield was inadequate. The key 18-membereding construction was significantly improved by employing the phenylthiophosphate-type substrates. When the substrates were activated by AgNO3 or I2 in the presence of molecular sieves in pyridine, the corresponding 18-membered ring products were obtained in high yields. Using this method as the key step, the chemically and biologically stable cADPR mimic, cADP-carbocyclic-ribose (cADPcR), was synthesized. This method has been applied subsequently to the synthesis of various cADPR analogs.

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“…The chemical synthetic method is now generally employed for synthesizing these types of biologically important cyclic nucleotides particularly those chemically modified in the N-1-linked ribose moiety, which are not expected to be accessible by an enzymatic route. [55][56][57][58][59][60][61][62][63][64][65][66] …”

Section: Resultsmentioning

confidence: 99%

Cyclic ADP-Carbocyclic-Ribose and -4-Thioribose, as Stable Mimics of Cyclic ADP-Ribose, a Ca<sup>2+</sup>-Mobilizing Second Messenger

Shuto

2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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Cyclic ADP-ribose (cADPR), a general mediator involved in Ca 2 signaling, has the characteristic 18-membered ring consisting of an adenine, two riboses and a pyrophosphate, in which the two primary hydroxy groups of the riboses are linked by a pyrophosphate unit. This review focuses on chemical synthetic studies of cADPR analogues of biological importance. Although cADPR analogues can be synthesized by enzymatic and chemo-enzymatic methods using ADP-ribosyl cyclase, the analogues obtained by these methods are limited due to the substrate-specificity of the enzymes. Consequently, chemical synthetic methods providing a greater variety of cADPR analogues are required. Although early chemical synthetic studies demonstrated that construction of the large 18-membered ring structure is difficult, the construction was achieved using the phenylthiophosphate-type substrates by treating with AgNO 3 or I 2 . This is now a general method for synthesizing these types of biologically important cyclic nucleotides. Using this method as the key step, the chemically and biologically stable cADPR mimic, cADP-carbocyclic-ribose (cADPcR) and -4-thioribose (cADPtR), were synthesized.

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Syntheses and Calcium-Mobilizing Evaluations of N-Glycosyl-Substituted Stable Mimics of Cyclic ADP-Ribose

Cited by 34 publications

References 32 publications

Amplification and propagation of pacemaker Ca2+ signals by cyclic ADP-ribose and the type 3 ryanodine receptor in T cells

Amplification and propagation of pacemaker Ca2+ signals by cyclic ADP-ribose and the type 3 ryanodine receptor in T cells

Chemistry of Cyclic ADP-Ribose and its Analogs

Cyclic ADP-Carbocyclic-Ribose and -4-Thioribose, as Stable Mimics of Cyclic ADP-Ribose, a Ca<sup>2+</sup>-Mobilizing Second Messenger

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