Abstract
d-myo-Inositol 1,4,5-trisphosphate receptors (IP3Rs) are Ca2+ channels activated by the intracellular messenger inositol 1,4,5-trisphosphate (IP3, 1). The glyconucleotide adenophostin A (AdA, 2) is a potent agonist of IP3Rs. A recent synthesis of d-chiro-inositol adenophostin (InsAdA, 5) employed suitably protected chiral building blocks and replaced the d-glucose core by d-chiro-inositol. An alternative approach to fully chiral material is now reported using intrinsic sugar chirality to avoid early isomer resolution, involving the coupling of a protected and activated racemic myo-inositol derivative to a d-ribose derivative. Diastereoisomer separation was achieved after trans-isopropylidene group removal and the absolute ribose–inositol conjugate stereochemistry assigned with reference to the earlier synthesis. Optimization of stannylene-mediated regiospecific benzylation was explored using the model 1,2-O-isopropylidene-3,6-di-O-benzyl-myo-inositol and conditions successfully transferred to one conjugate diastereoisomer with 3:1 selectivity. However, only roughly 1:1 regiospecificity was achieved on the required diastereoisomer. The conjugate regioisomers of benzyl derivatives 39 and 40 were successfully separated and 39 was transformed subsequently to InsAdA after amination, pan-phosphorylation, and deprotection. InsAdA from this synthetic route bound with greater affinity than AdA to IP3R1 and was more potent in releasing Ca2+ from intracellular stores through IP3Rs. It is the most potent full agonist of IP3R1 known and .equipotent with material from the fully chiral synthetic route.
Highlights
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels
Missing the adenine base, the corresponding D-chiro-inositol ribophostin counterpart (Figure 1, compound 4a) is the most potent small-molecule IP3 receptor agonist without a nucleobase yet synthesized, with potency and binding affinity for IP3R approaching those of AdA.[36]
We report an alternative synthetic strategy employing intrinsic D-ribose chirality and involving the separation of the diastereoisomers of a suitably protected chiro-inositol-ribonucleoside conjugate derived from a racemic myo-inositol building block
Summary
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels. In most animal cells, IP3Rs release Ca2+ from the endoplasmic reticulum (ER) in response to the many extracellular stimuli that evoke formation of D-myo-inositol. Missing the adenine base, the corresponding D-chiro-inositol ribophostin counterpart (Figure 1, compound 4a) is the most potent small-molecule IP3 receptor agonist without a nucleobase yet synthesized, with potency and binding affinity for IP3R approaching those of AdA.[36]. The present synthetic route should offer a somewhat more economical and practical approach than that reported earlier,[35] especially to the anticipated further analogues of this highly potent ligand and those exploiting substitutions on the 6′′-axial hydroxyl group that replaces the pyranoside ring oxygen of AdA This broad synthetic approach may be applicable to such analogues of D-chiroinositol ribophostin (Figure 1, compound 4a),[36] a related and simpler ligand that showed unexpectedly potent InsP3R activity in comparison to its disaccharide counterpart ribophostin and worthy of further development. The potential for using InsAdA to design further ligands of interest is recognized, the obvious difficulty and length of the synthetic procedures to access InsAdA analogues may well be a limiting factor in progressing this series
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