New Linear Precursors of cIDPR Derivatives as Stable Analogs of cADPR: A Potent Second Messenger with Ca2+-Modulating Activity Isolated from Sea Urchin Eggs.

Stefano D’Errico,Nicola Borbone,Tullio Pozzan,Gennaro Piccialli,Maria Marzano,Giorgia Oliviero,Vincenzo Piccialli,Andrea Patrizia Falanga,Emy Basso

doi:10.3390/md17080476

Abstract

Herein, we report on the synthesis of a small set of linear precursors of an inosine analogue of cyclic ADP-ribose (cADPR), a second messenger involved in Ca2+ mobilization from ryanodine receptor stores firstly isolated from sea urchin eggs extracts. The synthesized compounds were obtained starting from inosine and are characterized by an N1-alkyl chain replacing the “northern” ribose and a phosphate group attached at the end of the N1-alkyl chain and/or 5′-sugar positions. Preliminary Ca2+ mobilization assays, performed on differentiated C2C12 cells, are reported as well.

Highlights

Ca2+ -mediated signaling is the major secondary messenger involved in several essential cell functions
Cellular Ca2+ mobilization is involved in several physio-pathological processes, and the discovery of molecules that could act as agonist or antagonist of cyclic ADP-ribose (cADPR) is an appealing goal for medicinal chemistry. cADPR has a unique structure, but its lability has strongly limited the comprehension of cellular mechanisms regulated by Ca2+ mobilization
We synthesized many cIDPR derivatives as stable mimics of cADPR, discovering that a pentyl chain replacing the “northern” ribose and one phosphate group could be sufficient to retain the biological activity in PC12 cells differentiated in neurons

Summary

Introduction

Ca2+ -mediated signaling is the major secondary messenger involved in several essential cell functions. Ca2+ ions are generally located in the endoplasmic reticulum (ER) and mitochondria until an extracellular stimulus causes their release into the cytosol [1,2] This mobilization may lead to a great number of physiological effects such as gene regulation [3], cell proliferation, fertilization [4], muscle contraction [5], and neurotransmitter secretion [6]. CADPR, together with inositol 1,4,5-triphosphate (IP3) and nicotinic acid adenine dinucleotide phosphate (NAADP), is a second messenger involved in cellular Ca2+ mobilization [12,13]. It interacts with ryanodine receptors through a mechanism which is.

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