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

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.

Synthetic cADPR analogues may form only one of two possible conformational diastereoisomers

“…These compounds have not yet all been synthesised, but the observations reported here may potentially contribute to the unexpected biological activity of some recent analogues we reported with a “northern” L-ribose 31 . Thus, an awareness of the possibility of different conformers and the potential implications for biological activity should be considered in any future cADPR analogue studies using total synthesis 19 , 21 , 23 , 31 – 33 . This may however be most relevant in situations where any “northern” ribose surrogate does not possess functional groups with the ability to “lock” the cyclisation precursor onto one face, as in Fig.…”

“…7 , and thus control the direction of ring closure. Examples here would be cIDPRE, where the “northern” ribose is a totally flexible ether chain 34 , cIDPDE with both riboses so replaced 35 and those similar compounds with both ether and alkane chain surrogates 22 , including more recent N 1-pentyl and corresponding phosphonopyrophosphate analogues 33 . It could well be pertinent now to re-examine the structures and activities of all such analogues in the light of this work.…”

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

“…Over the last years, our research group synthesized several cIDPR analogues [30,31,32,33,34,35,36,37]. In particular, the pyrophosphate (cpIDP, 3 , Figure 1) [30] and the monophosphate (cpIMP, 4 , Figure 1) [36] derivatives with a pentyl chain replacing the “northern” ribose showed interesting Ca 2+ -releasing activities in PC12 cells differentiated in neurons with the use of nerve growth factor (NGF) [18].…”

“…In particular, the pyrophosphate (cpIDP, 3 , Figure 1) [30] and the monophosphate (cpIMP, 4 , Figure 1) [36] derivatives with a pentyl chain replacing the “northern” ribose showed interesting Ca 2+ -releasing activities in PC12 cells differentiated in neurons with the use of nerve growth factor (NGF) [18]. Meanwhile, the pyrophosphate derivative with a butyl chain in the place of the “northern” ribose was inactive on the same cell line [37]. In addition, we synthesized the derivative 5 (Figure 1), bearing a phosphono-phosphate anhydride in the place of the pyrophosphate, with the aim of better exploring the role of the pyrophosphate in Ca 2+ -mobilizing properties of cADPR/cIDPR analogues [37].…”

“…Meanwhile, the pyrophosphate derivative with a butyl chain in the place of the “northern” ribose was inactive on the same cell line [37]. In addition, we synthesized the derivative 5 (Figure 1), bearing a phosphono-phosphate anhydride in the place of the pyrophosphate, with the aim of better exploring the role of the pyrophosphate in Ca 2+ -mobilizing properties of cADPR/cIDPR analogues [37]. Unfortunately, the compound 5 also failed to modify the [Ca 2+ ] i in PC12 cells.…”