Journal article
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 regioisomers were successfully separated and 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 and was equipotent with material from the fully chiral synthetic route.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 2.6MB, Terms of use)
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- Publisher copy:
- 10.1021/acsomega.0c04145
Authors
- Publisher:
- American Chemical Society
- Journal:
- ACS Omega More from this journal
- Volume:
- 5
- Issue:
- 44
- Pages:
- 28793–28811
- Publication date:
- 2020-10-28
- Acceptance date:
- 2020-10-08
- DOI:
- EISSN:
-
2470-1343
- Language:
-
English
- Keywords:
- Pubs id:
-
1136453
- Local pid:
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pubs:1136453
- Deposit date:
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2020-10-08
Terms of use
- Copyright holder:
- American Chemical Society
- Copyright date:
- 2020
- Rights statement:
- ©2020 American Chemical Society
- Notes:
- This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
- Licence:
- CC Attribution (CC BY)
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