Inositol adenophostin: convergent synthesis of a potent agonist of D-myo-inositol 1,4,5-trisphosphate receptors
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 su...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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American Chemical Society
2020
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| _version_ | 1826268122775027712 |
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| author | Su, X Dohle, W Mills, S Potter, B |
| author_facet | Su, X Dohle, W Mills, S Potter, B |
| author_sort | Su, X |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:04:45Z |
| format | Journal article |
| id | oxford-uuid:3c1184dc-4993-4144-b3bb-d8b9d4093eea |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:04:45Z |
| publishDate | 2020 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:3c1184dc-4993-4144-b3bb-d8b9d4093eea2022-03-26T14:11:25ZInositol adenophostin: convergent synthesis of a potent agonist of D-myo-inositol 1,4,5-trisphosphate receptorsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3c1184dc-4993-4144-b3bb-d8b9d4093eeaEnglishSymplectic ElementsAmerican Chemical Society2020Su, XDohle, WMills, SPotter, BD-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. |
| spellingShingle | Su, X Dohle, W Mills, S Potter, B Inositol adenophostin: convergent synthesis of a potent agonist of D-myo-inositol 1,4,5-trisphosphate receptors |
| title | Inositol adenophostin: convergent synthesis of a potent agonist of D-myo-inositol 1,4,5-trisphosphate receptors |
| title_full | Inositol adenophostin: convergent synthesis of a potent agonist of D-myo-inositol 1,4,5-trisphosphate receptors |
| title_fullStr | Inositol adenophostin: convergent synthesis of a potent agonist of D-myo-inositol 1,4,5-trisphosphate receptors |
| title_full_unstemmed | Inositol adenophostin: convergent synthesis of a potent agonist of D-myo-inositol 1,4,5-trisphosphate receptors |
| title_short | Inositol adenophostin: convergent synthesis of a potent agonist of D-myo-inositol 1,4,5-trisphosphate receptors |
| title_sort | inositol adenophostin convergent synthesis of a potent agonist of d myo inositol 1 4 5 trisphosphate receptors |
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