d-chiro-Inositol Ribophostin: A Highly Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors: Synthesis and Biological Activities

Analogues of the Ca2+-releasing intracellular messenger d-myo-inositol 1,4,5-trisphosphate [1, Ins­(1,4,5)­P3] 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 p...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2020-03, Vol.63 (6), p.3238-3251
Main Authors: Mills, Stephen J, Rossi, Ana M, Konieczny, Vera, Bakowski, Daniel, Taylor, Colin W, Potter, Barry V. L
Format: Article
Language:English
Subjects:
Animals
Calcium - metabolism
Cell Line
Chickens
Humans
Inositol 1,4,5-Trisphosphate Receptors - agonists
Inositol Phosphates - chemical synthesis
Inositol Phosphates - pharmacology
Molecular Structure
Rats
Ribosemonophosphates - chemical synthesis
Ribosemonophosphates - pharmacology
Structure-Activity Relationship
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Summary:Analogues of the Ca2+-releasing intracellular messenger d-myo-inositol 1,4,5-trisphosphate [1, Ins­(1,4,5)­P3] 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)­P3 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 Ca2+-release assays; its potency and binding affinity for Ins­(1,4,5)­P3R were similar to those of adenophostin. Both 4 and 10 elicited a store-operated Ca2+ current ICRAC in patch-clamped cells, unlike Ins­(1,4,5)­P3 consistent with resistance to metabolism. d-chiro-Inositol ribophostin is the most potent small-molecule Ins­(1,4,5)­P3 receptor agonist without a nucleobase yet synthesized.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b01986