Synthesis and Biological Evaluation of a New Structural Simplified Analogue of cADPR, a Calcium-Mobilizing Secondary Messenger Firstly Isolated from Sea Urchin Eggs.

Stefano D’Errico,Gennaro Piccialli,Giorgia Oliviero,Agnese Secondo,Bruno Catalanotti,Luciano Mayol,Valeria Costantino,Anna Pannaccione,Ilaria Piccialli,Tiziana Petrozziello,Nicola Borbone

doi:10.3390/md16030089

Stefano D’Errico, Gennaro Piccialli + Show 9 more

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https://doi.org/10.3390/md16030089

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Abstract

Herein, we reported on the synthesis of cpIPP, which is a new structurally-reduced analogue of cyclic ADP-ribose (cADPR), a potent Ca2+-releasing secondary messenger that was firstly isolated from sea urchin eggs extracts. To obtain cpIPP the “northern” ribose of cADPR was replaced by a pentyl chain and the pyrophosphate moiety by a phophono-phosphate anhydride. The effect of the presence of the new phosphono-phosphate bridge on the intracellular Ca2+ release induced by cpIPP was assessed in PC12 neuronal cells in comparison with the effect of the pyrophosphate bridge of the structurally related cyclic N1-butylinosine diphosphate analogue (cbIDP), which was previously synthesized in our laboratories, and with that of the linear precursor of cpIPP, which, unexpectedly, revealed to be the only one provided with Ca2+ release properties.

Highlights

Abstract: we reported on the synthesis of cpIPP, which is a new structurally-reduced analogue of cyclic ADP-ribose, a potent Ca2+-releasing secondary messenger that was firstly isolated from sea urchin eggs extracts
Cyclic ADP-ribose is a natural occurring metabolite of NAD+ that is capable of mobilizing Ca2+ ions from intracellular stores. cyclic ADP-ribose (cADPR) was firstly isolated from sea urchin eggs extracts [1,2,3,4,5,6], but it was later established that it is produced in many other mammalian cells, including pancreatic β-cells, T-lymphocytes, smooth and cardiac muscle cells, and cerebellar neurons, acting as a Ca2+-mobilizing agent [7,8,9]
CADPR has been classified as a second messenger that, activating the ryanodine receptors of the sarcoplasmic reticulum, is able to mobilize the calcium ions from the intracellular stores [10]. cADPR is involved in many physiological processes that are related to the variation of the Ca2+ concentration, such as the synaptic homeostasis in neurons [11], as well as fertilization and cellular

Summary

Introduction

Cyclic ADP-ribose (cADPR, 1, Figure 1) is a natural occurring metabolite of NAD+ that is capable of mobilizing Ca2+ ions from intracellular stores. cADPR was firstly isolated from sea urchin eggs extracts [1,2,3,4,5,6], but it was later established that it is produced in many other mammalian cells, including pancreatic β-cells, T-lymphocytes, smooth and cardiac muscle cells, and cerebellar neurons, acting as a Ca2+-mobilizing agent [7,8,9]. To further explore the role of the pyrophosphate group in the biological activity of cADPR analogues, we report on the synthesis and chemical and biological characterization of a new cyclic N1-pentyl inosine phosphono-phosphate anhydride analogue, cpIPP (13), in which the northern phosphate of 11 was replaced by a C-phosphonate moiety. This kind of modification is unprecedented and adds a further piece of information on the SAR of Ca2+ releasing cADPR analogues. The Ca2+ mobilizing activities in PC12 cells of compounds 13 and of its linear precursor, as well as of the previously synthesized cyclic N1-butyl derivative 10 [35], which shares with the compound 13 the ring size, are reported

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Conclusions