Synthesis of glucopyranoside-based ligands for D-myo-inositol 1,4,5-trisphosphate receptors.
Adenophostins A and B are naturally occurring glyconucleotides that interact potently with receptors for D-myo-inositol 1,4,5-trisphosphate, an important second messenger molecule in most cell types. Here we describe the design and synthesis of glucopyranoside-based analogues of adenophostin A lacking the adenine component. The key synthetic strategy involves glycosylation of selectively protected alcohols, derived from methyl beta-D-ribofuranoside or 1,4-anhydroerythritol, using glycosyl donors synthesised from 2,6-di-O-benzyl-D-glucopyranose derivatives. Further elaboration and deprotection of the coupled products gave two trisphosphate analogues; methyl 3-O-alpha-D-glucopyranosyl-beta-D-ribofuranoside 2,3',4'-trisphosphate ("ribophostin") and (3'S,4'R)-3'-hydroxytetrahydrofuran-4'-yl alpha-D-glucopyranoside 3,4,3'-trisphosphosphate ("furanophostin"). The route to furanophostin was further modified to give (3'S,4'R)-3'-hydroxytetrahydrofuran-4'-yl alpha-D-glucopyranoside 3'-phosphate 3,4-bisphosphorothioate, the first phosphorothioate-containing adenophostin analogue.
Riley
Andrew M
AM
Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, UK.
Jenkins
David J
DJ
Marwood
Rachel D
RD
Potter
Barry V L
BV
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002855:Chromatography, Thin Layer; D005936:Glucans / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands; D015394:Molecular Structure; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*
D002120:Calcium Channel Agonists; D015220:Calcium Channels; D005936:Glucans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; C085029:adenophostin A; C008763:panose; D000241:Adenosine