Abstract
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.
Highlights
Phospholipase C hydrolyzes phosphatidylinositol 4,5-bisphosphate to release the water-soluble second messenger, D-myoinositol 1,4,5-trisphosphate [Ins(1,4,5)P3 1, Figure 1]
We report a synthesis of Dchiro-inositol ribophostin 10 and demonstrate that it both binds with greater affinity than ribophostin to Ins(1,4,5)P3R and more potently evokes Ca2+ release, confirming the value of our approach
The presence of the ribose attached to the D-chiro-inositol derivative via an ether seemed to affect the ease with which the trans-isopropylidene acetal was removed by acid in the presence of ethylene glycol
Summary
Phospholipase C hydrolyzes phosphatidylinositol 4,5-bisphosphate to release the water-soluble second messenger, D-myoinositol 1,4,5-trisphosphate [Ins(1,4,5)P3 1, Figure 1]. The skeletal tetrahydrofuran derivative such as 8 (Figure 2) exhibits a potency close to Ins(1,4,5)P3 and ribophostin.[11] There is little effect when the primary hydroxymethyl groups are removed either individually or together.[19] If 3,4-bisphosphate is replaced with bis-phosphorothioate,[19] EC50 drops 5-fold. D-chiro-Inositol adenophostin 4 was the first adenophostin A analogue of its kind to possess a glucose-to-inositol replacement, offering increased possibilities for structural diversity and engineering by virtue of its extra hydroxyl group replacing the pyranoside oxygen This confirms the high activity of 10 but suggests it to be substantially hydrolysis-resistant in whole cells, potentially enhancing its value along with 4 as an investigative tool for chemical biology
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