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Inositol Adenophostin: Convergent Synthesis of a Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors.


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.

SUBMITTER: Su X 

PROVIDER: S-EPMC7659177 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Inositol Adenophostin: Convergent Synthesis of a Potent Agonist of d-<i>myo</i>-Inositol 1,4,5-Trisphosphate Receptors.

Su Xiangdong X   Dohle Wolfgang W   Mills Stephen J SJ   Watt Joanna M JM   Rossi Ana M AM   Taylor Colin W CW   Potter Barry V L BVL  

ACS omega 20201028 44


d-<i>myo</i>-Inositol 1,4,5-trisphosphate receptors (IP<sub>3</sub>Rs) are Ca<sup>2+</sup> channels activated by the intracellular messenger inositol 1,4,5-trisphosphate (IP<sub>3</sub>, <b>1</b>). The glyconucleotide adenophostin A (AdA, <b>2</b>) is a potent agonist of IP<sub>3</sub>Rs. A recent synthesis of d-<i>chiro</i>-inositol adenophostin (InsAdA, <b>5</b>) employed suitably protected chiral building blocks and replaced the d-glucose core by d-<i>chiro</i>-inositol. An alternative approa  ...[more]

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