Synthesis of cyclic N (1)-pentylinosine phosphate, a new structurally reduced cADPR analogue with calcium-mobilizing activity on PC12 cells.

Ahmed Mahal,Valentina Tedeschi,Giorgia Oliviero,Valeria Costantino,Stefano D’Errico,Brunella Pinto,Vincenzo Piccialli,Nicola Borbone,Agnese Secondo,Gennaro Piccialli

doi:10.3762/bjoc.11.289

Ahmed Mahal, Valentina Tedeschi + Show 8 more

Open Access

https://doi.org/10.3762/bjoc.11.289

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Abstract

Cyclic N1-pentylinosine monophosphate (cpIMP), a novel simplified inosine derivative of cyclic ADP-ribose (cADPR) in which the N1-pentyl chain and the monophosphate group replace the northern ribose and the pyrophosphate moieties, respectively, was synthesized. The role played by the position of the phosphate group in the key cyclization step, which consists in the formation of a phosphodiester bond, was thoroughly investigated. We have also examined the influence of the phosphate bridge on the ability of cpIMP to mobilize Ca2+ in PC12 neuronal cells in comparison with the pyrophosphate bridge present in the cyclic N1-pentylinosine diphosphate analogue (cpIDP) previously synthesized in our laboratories. The preliminary biological tests indicated that cpIMP and cpIDP induce a rapid increase of intracellular Ca2+ concentration in PC12 neuronal cells.

Highlights

Nucleosides and nucleotides (NNs) are widely used as key intermediates and important core structures in the field of synthetic medicinal chemistry [1,2]
We have examined the influence of the phosphate bridge on the ability of Cyclic N1-pentylinosine monophosphate (cpIMP) to mobilize Ca2+ in PC12 neuronal cells in comparison with the pyrophosphate bridge present in the cyclic N1-pentylinosine diphosphate analogue previously synthesized in our laboratories
Among these NNs there is the cyclic ADP-ribose, a metabolite strictly involved in the homeostasis of cellular calcium ions. cADPR is a second messenger that activates the ryanodine receptors of the sarcoplasmic reticulum and mobilizes Ca2+ ions in many cell types of protozoa, plants, animals and humans [13]

Summary

Introduction

Nucleosides and nucleotides (NNs) are widely used as key intermediates and important core structures in the field of synthetic medicinal chemistry [1,2]. We have examined the influence of the phosphate bridge on the ability of cpIMP to mobilize Ca2+ in PC12 neuronal cells in comparison with the pyrophosphate bridge present in the cyclic N1-pentylinosine diphosphate analogue (cpIDP) previously synthesized in our laboratories. The preliminary biological tests indicated that cpIMP and cpIDP induce a rapid increase of intracellular Ca2+ concentration in PC12 neuronal cells.

Results

Conclusion