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

Abstract

Analogues of the Ca 2+ -releasing intracellular messenger D-myoinositol 1,4,5-trisphosphate [1, Ins(1,4,5)P 3 ] 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)P 3 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 Ca 2+ -release assays; its potency and binding affinity for Ins(1,4,5)P 3 R were similar to those of adenophostin. Both 4 and 10 elicited a store-operated Ca 2+ current I CRAC in patch-clamped cells, unlike Ins(1,4,5)P 3 consistent with resistance to metabolism. D-chiro-Inositol ribophostin is the most potent small-molecule Ins(1,4,5)P 3 receptor agonist without a nucleobase yet synthesized.

Biological Regulatory Network (BRN) Analysis and Molecular Docking Simulations to Probe the Modulation of IP3R Mediated Ca2+ Signaling in Cancer

“…Early studies about IP 3 R [ 113 , 114 , 115 ] demonstrated that the IP 3 molecule mostly interacts with its receptor in stereospecific manner, where R 4 and R 5 vicinal phosphate groups are considered as a pivotal structural feature in defining binding specificity [ 115 ]. Recently, the findings of Mills et al [ 49 ] also prove the importance of these positions in Ca +2 release activity.…”

“…Furthermore, phosphate group present at the positions R 4 and R 5 are considered important in IP 3 binding with its receptor as described in different studies [ 49 , 87 ]. Despite the difference in stereochemistry, the R 4 phosphate group of all compounds either most active or least active interacted with the receptor in a favored manner.…”

“…Moreover, the phosphate group at position R 1 is considered an important group to improve the IP 3 binding affinity with its receptor [ 116 ]. Recently, Mills and coworkers [ 49 ] found that the deletion of phosphate group from this position may result in the reduction of inhibitory potency. Similarly, bis-1-oxaquinolizidines Xestospongin derivatives are considered to provide an ideal lipophilic interaction within the binding pocket of IP 3 R. The addition of a hydrogen bond donor at position R 5 of oxaquinolizidines ring structure is associated with the decrease of potency by two-folds [ 90 ].…”

“…A dataset ( Supplementary excel file ) of already known 40 inositol analogs, cyclic quinolizidines, and other structurally diverse compounds, with known inhibitory potency (IC 50 ) values against IP 3 R was collected from literature [ 31 , 45 , 46 , 47 , 48 , 49 ] and from the ChEMBL database [ 50 ]. The dataset includes only those competitive inhibitors of IP 3 binding for which inhibitory potency against IP 3 R was calculated by fluorescence assay [ 51 , 52 ].…”

Both d- and l-Glucose Polyphosphates Mimic d-myo-Inositol 1,4,5-Trisphosphate: New Synthetic Agonists and Partial Agonists at the Ins(1,4,5)P3 Receptor

“…Results from binding experiments are means ± SEM (p K d (−log of the equilibrium dissociation constant) and h ) and means ( K d ) from three independent experiments. The p K d values for Ins­(1,4,5)­P 3 and AdA have been published (Mills et al) and are reproduced with permission. Final columns show EC 50 / K d or (for partial agonists and Ins­(1,4,5)­P 3 ) EC 39 / K d (mean and 95% CI).…”