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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...

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Autores principales: Mills, Stephen J., Rossi, Ana M., Konieczny, Vera, Bakowski, Daniel, Taylor, Colin W., Potter, Barry V. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
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.
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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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