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d-chiro-Inositol Ribophostin: A Highly Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors: Synthesis and Biological Activities
[Image: see text] Analogues of the Ca(2+)-releasing intracellular messenger d-myo-inositol 1,4,5-trisphosphate [1, Ins(1,4,5)P(3)] are important synthetic targets. Replacement of the α-glucopyranosyl motif in the natural product mimic adenophostin 2 by d-chiro-inositol in d-chiro-inositol adenophost...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104261/ https://www.ncbi.nlm.nih.gov/pubmed/32052631 http://dx.doi.org/10.1021/acs.jmedchem.9b01986 |
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author | Mills, Stephen J. Rossi, Ana M. Konieczny, Vera Bakowski, Daniel Taylor, Colin W. Potter, Barry V. L. |
author_facet | Mills, Stephen J. Rossi, Ana M. Konieczny, Vera Bakowski, Daniel Taylor, Colin W. Potter, Barry V. L. |
author_sort | Mills, Stephen J. |
collection | PubMed |
description | [Image: see text] Analogues of the Ca(2+)-releasing intracellular messenger d-myo-inositol 1,4,5-trisphosphate [1, Ins(1,4,5)P(3)] are important synthetic targets. Replacement of the α-glucopyranosyl motif in the natural product mimic adenophostin 2 by d-chiro-inositol in d-chiro-inositol adenophostin 4 increased the potency. Similar modification of the non-nucleotide Ins(1,4,5)P(3) mimic ribophostin 6 may increase the activity. d-chiro-Inositol ribophostin 10 was synthesized by coupling as building blocks suitably protected ribose 12 with l-(+)-3-O-trifluoromethylsulfonyl-6-O-p-methoxybenzyl-1,2:4,5-di-O-isopropylidene-myo-inositol 11. Separable diastereoisomeric 3-O-camphanate esters of (±)-6-O-p-methoxy-benzyl-1,2:4,5-di-O-isopropylidene-myo-inositol allowed the preparation of 11. Selective trans-isopropylidene deprotection in coupled 13, then monobenzylation gave separable regioisomers 15 and 16. p-Methoxybenzyl group deprotection of 16, phosphitylation/oxidation, then deprotection afforded 10, which was a full agonist in Ca(2+)-release assays; its potency and binding affinity for Ins(1,4,5)P(3)R were similar to those of adenophostin. Both 4 and 10 elicited a store-operated Ca(2+) current I(CRAC) in patch-clamped cells, unlike Ins(1,4,5)P(3) consistent with resistance to metabolism. d-chiro-Inositol ribophostin is the most potent small-molecule Ins(1,4,5)P(3) receptor agonist without a nucleobase yet synthesized. |
format | Online Article Text |
id | pubmed-7104261 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-71042612020-03-31 d-chiro-Inositol Ribophostin: A Highly Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors: Synthesis and Biological Activities Mills, Stephen J. Rossi, Ana M. Konieczny, Vera Bakowski, Daniel Taylor, Colin W. Potter, Barry V. L. J Med Chem [Image: see text] Analogues of the Ca(2+)-releasing intracellular messenger d-myo-inositol 1,4,5-trisphosphate [1, Ins(1,4,5)P(3)] are important synthetic targets. Replacement of the α-glucopyranosyl motif in the natural product mimic adenophostin 2 by d-chiro-inositol in d-chiro-inositol adenophostin 4 increased the potency. Similar modification of the non-nucleotide Ins(1,4,5)P(3) mimic ribophostin 6 may increase the activity. d-chiro-Inositol ribophostin 10 was synthesized by coupling as building blocks suitably protected ribose 12 with l-(+)-3-O-trifluoromethylsulfonyl-6-O-p-methoxybenzyl-1,2:4,5-di-O-isopropylidene-myo-inositol 11. Separable diastereoisomeric 3-O-camphanate esters of (±)-6-O-p-methoxy-benzyl-1,2:4,5-di-O-isopropylidene-myo-inositol allowed the preparation of 11. Selective trans-isopropylidene deprotection in coupled 13, then monobenzylation gave separable regioisomers 15 and 16. p-Methoxybenzyl group deprotection of 16, phosphitylation/oxidation, then deprotection afforded 10, which was a full agonist in Ca(2+)-release assays; its potency and binding affinity for Ins(1,4,5)P(3)R were similar to those of adenophostin. Both 4 and 10 elicited a store-operated Ca(2+) current I(CRAC) in patch-clamped cells, unlike Ins(1,4,5)P(3) consistent with resistance to metabolism. d-chiro-Inositol ribophostin is the most potent small-molecule Ins(1,4,5)P(3) receptor agonist without a nucleobase yet synthesized. American Chemical Society 2020-02-13 2020-03-26 /pmc/articles/PMC7104261/ /pubmed/32052631 http://dx.doi.org/10.1021/acs.jmedchem.9b01986 Text en Copyright © 2020 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Mills, Stephen J. Rossi, Ana M. Konieczny, Vera Bakowski, Daniel Taylor, Colin W. Potter, Barry V. L. d-chiro-Inositol Ribophostin: A Highly Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors: Synthesis and Biological Activities |
title | d-chiro-Inositol Ribophostin:
A Highly Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors:
Synthesis and Biological Activities |
title_full | d-chiro-Inositol Ribophostin:
A Highly Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors:
Synthesis and Biological Activities |
title_fullStr | d-chiro-Inositol Ribophostin:
A Highly Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors:
Synthesis and Biological Activities |
title_full_unstemmed | d-chiro-Inositol Ribophostin:
A Highly Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors:
Synthesis and Biological Activities |
title_short | d-chiro-Inositol Ribophostin:
A Highly Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors:
Synthesis and Biological Activities |
title_sort | d-chiro-inositol ribophostin:
a highly potent agonist of d-myo-inositol 1,4,5-trisphosphate receptors:
synthesis and biological activities |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104261/ https://www.ncbi.nlm.nih.gov/pubmed/32052631 http://dx.doi.org/10.1021/acs.jmedchem.9b01986 |
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