A synthetic cyclitol-nucleoside conjugate polyphosphate is a highly potent second messenger mimic. Issue 20 (1st May 2019)

• Record Type: Journal Article
• Authors: Dohle, Wolfgang; Su, Xiangdong; Mills, Stephen J.; Rossi, Ana M.; Taylor, Colin W.; Potter, Barry V. L.
• Is Part Of: Chemical science. Volume 10:Issue 20(2019)
• Page Start: 5382
• Page End: 5390
• Publication Date: 2019-05-01
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c9sc00445a
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : A densely functionalised phosphorylated chiro -inositol-nucleoside ether conjugate constructed from cyclic fragments is the most potent IP3 receptor ligand discovered. Abstract : Reactions that form sec – sec 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 potentd - myo -inositol 1, 4, 5-trisphosphate (IP3 R) agonist, with ad - 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 ofd - chiro -inositol and the 3′-hydroxyl group of an adenosine ribose sugar. A divergent synthesis ofd - 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 tol -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 sec – sec 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 N 6 protection/deprotection strategy.d - chiro -Inositol adenophostin evoked Ca 2+ release through IP3 Rs at lower concentrations than adenophostin A, hitherto the most potent known agonist of IP3 Rs.