Synthesis of cyclic N¹-pentylinosine phosphate, a new structurally reduced cADPR analogue with calcium-mobilizing activity on PC12 cells

Abstract

SummaryCyclic N 1-pentylinosine monophosphate (cpIMP), a novel simplified inosine derivative of cyclic ADP-ribose (cADPR) in which the N 1-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 N 1-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.

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

“…Compounds 11 and 14 were synthesized starting from the versatile building block 6 (Scheme 1), readily obtained from inosine [36].…”

“…Desilylation with TBAF of 12a – c to afford 13a – c , followed by the usual acidic treatment, yielded compounds 14a – c almost quantitatively. For the synthesis of nucleotide 16 (Scheme 2), we started from the intermediate 15 , useful for the synthesis of cpIMP 4 [36]. The acidic treatment on 15 afforded directly the target 16 (99% yield).…”

“…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]. Meanwhile, the pyrophosphate derivative with a butyl chain in the place of the “northern” ribose was inactive on the same cell line [37].…”

Calcium‐Mobilizing Behaviors of Neutral Cyclic ADP‐Ribose Mimics that Integrate Modifications to the Nucleobase, Northern Ribose and Pyrophosphate

“…Cyclic ATP‐ribose (cATPR), with a triphosphate bridge, for example, was shown to be considerably more potent than cADPR in inducing Ca 2+ release from rat brain microsomes . Agonistic activity was also retained when the pyrophosphate linkage was shrunk to a monophosphate . Sulfur‐ and selenium‐substituted cyclic pyrophosphate cIDPRE derivatives also lowered the agonistic activity .…”

Second messenger analogues highlight unexpected substrate sensitivity of CD38: total synthesis of the hybrid “L-cyclic inosine 5′-diphosphate ribose”

“…Many total synthetic routes to cADPR analogues required considerable modification of the “northern” ribose in order to generate a stable N 1-link 30 – 34 . The difficulty of selective N 1-ribosylation meant that this tended to be the site at which structural modifications were carried out to overcome issues with synthetic tractability.…”