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Issue 20, 2019
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A synthetic cyclitol-nucleoside conjugate polyphosphate is a highly potent second messenger mimic

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Abstract

Reactions that form secsec ethers are well known, but few lead to compounds with dense functionality around the O-linkage. Replacement of the α-glucopyranosyl unit of adenophostin A, a potent D-myo-inositol 1,4,5-trisphosphate (IP3R) agonist, with a D-chiro-inositol surrogate acting substantially as a pseudosugar, leads to “D-chiro-inositol adenophostin”. At its core, this cyclitol-nucleoside trisphosphate comprises an ether linkage between the axial 1-hydroxyl position of D-chiro-inositol and the 3′-hydroxyl group of an adenosine ribose sugar. A divergent synthesis of D-chiro-inositol adenophostin has been achieved. Key features of the synthetic strategy to produce a triol for phosphorylation include a new selective mono-tosylation of racemic 1,2:4,5-di-O-isopropylidene-myo-inositol using tosyl imidazole; subsequent conversion of the product into separable camphanate ester derivatives, one leading to a chiral myo-inositol triflate used as a synthetic building block and the other to L-1-O-methyl-myo-inositol [L-(+)-bornesitol] to assign the absolute configuration; the nucleophilic coupling of an alkoxide of a ribose pent-4-ene orthoester unit with a structurally rigid chiral myo-inositol triflate derivative, representing the first secsec ether formation between a cyclitol and ribose. Reaction of the coupled product with a silylated nucleobase completes the assembly of the core structure. Further protecting group manipulation, mixed O- and N-phosphorylation, and subsequent removal of all protecting groups in a single step achieves the final product, avoiding a separate N6 protection/deprotection strategy. D-chiro-Inositol adenophostin evoked Ca2+ release through IP3Rs at lower concentrations than adenophostin A, hitherto the most potent known agonist of IP3Rs.

Graphical abstract: A synthetic cyclitol-nucleoside conjugate polyphosphate is a highly potent second messenger mimic

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Supplementary files

Article information


Submitted
25 Jan 2019
Accepted
23 Apr 2019
First published
23 Apr 2019

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2019,10, 5382-5390
Article type
Edge Article

A synthetic cyclitol-nucleoside conjugate polyphosphate is a highly potent second messenger mimic

W. Dohle, X. Su, S. J. Mills, Ana M. Rossi, C. W. Taylor and B. V. L. Potter, Chem. Sci., 2019, 10, 5382
DOI: 10.1039/C9SC00445A

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