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

Analogues of the Ca-releasing intracellular messenger d--inositol 1,4,5-trisphosphate [, Ins(1,4,5)P] are important synthetic targets. Replacement of the α-glucopyranosyl motif in the natural product mimic adenophostin by d--inositol in d--inositol adenophostin increased the potency. Similar modification of the non-nucleotide Ins(1,4,5)P mimic ribophostin may increase the activity. d--Inositol ribophostin was synthesized by coupling as building blocks suitably protected ribose with l-(+)-3--trifluoromethylsulfonyl-6---methoxybenzyl-1,2:4,5-di--isopropylidene--inositol . Separable diastereoisomeric 3--camphanate esters of (±)-6---methoxy-benzyl-1,2:4,5-di--isopropylidene--inositol allowed the preparation of . Selective -isopropylidene deprotection in coupled , then monobenzylation gave separable regioisomers and . -Methoxybenzyl group deprotection of , phosphitylation/oxidation, then deprotection afforded , which was a full agonist in Ca-release assays; its potency and binding affinity for Ins(1,4,5)PR were similar to those of adenophostin. Both and elicited a store-operated Ca current I in patch-clamped cells, unlike Ins(1,4,5)P consistent with resistance to metabolism. d--Inositol ribophostin is the most potent small-molecule Ins(1,4,5)P receptor agonist without a nucleobase yet synthesized.