Synthesis of D-3-deoxy-myo-inositol 1,4,5-trisphosphate and its effect on Ca2+ release in NIH 3T3 cells

Seewald, M. J.; Aksoy, Ibrahim A.; Powis, Garth; Fauq, Abdul H.; Kozikowski, Alan P.

doi:10.1039/c39900001638

Cited by 24 publications

(17 citation statements)

References 8 publications

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“…Alternatively, they may act to fix the solution conformation of Ins (1,4,5)P3 by intramolecular hydrogen bonding to the neighbouring phosphates [15]. The axial 2-hydroxyl (2-OH) and equatorial 3-OH do not appear to be critical for Ins(l,4,5)P3 receptor binding and Cazi release since ~~-2 -d e o x y - [16], 3-deoxy-E!7, 181, and 2,3-dideoxy-Ins(l,4,5)P3 [17,181 are all potent Bcs(l,4,5)P3 receptor ligands and agonists. In contrast with the 2-OH and 3-OH groups, the 6-OH group appears to make a more significant contribution to receptor interaction, since 6-deoxy-[I91 and 2,3,6-trideoxy- [18,201 are both weak ligands and agonists.…”

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confidence: 99%

Modification at C2 of myo‐inositol 1,4,5‐trisphosphate produces inositol trisphosphates and tetrakisphosphates with potent biological activities

Wilcox

Safrany

Lampe

et al. 1994

European Journal of Biochemistry

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. sc-Ins(1,2,4,5)P4 was equipotent to Ins(1,4,5)P3 for Ca2+ release making it the most potent inositol tetrakisphosphate and indeed Ins(3 ,4,5)P3 analogue yet characterised. In contrast, although sc-Ins(l,2,4,5)PS4 (IC,, 425 nM, EC501603 nM) was a significantly weaker ligand and agonist than Ins(1,4,5)P3, it was a partial agonist of high intrinsic activity with maximally effective concentrations releasing only about 80% of Ins(1 ,4,5)P3-sensitive Ca2+ stores of SH-SY5Y cells. Ins(1 ,4,5)P3 and sc-Ins(1 ,2,4,5)P4 were readily metabolised by Ins(1 ,4,5)P3 3-kinase and 5-phosphatase activities, ~~-2 F -I n s ( l ,4,5)P3 and DL-sc-Ins( 1 ,2,4)P3 were resistant to 5-phosphatase, while sc-Ins( 1 ,2,4,5)PS4 and DL-Ins( 1,2,4,5)P, were resistant to both 3-kinase and 5-phosphatase activity and were potent inhibitors of the 5-phosphatase enzyme (Kl = 300 nM and 2.9 pM, respectively). These results demonstrate that modification of the 2-position of Ins( 1 ,4,5)P3, even with an anionic group, does not critically affect Ins( 1 ,4,5)P3 receptor binding interaction or Ca2+ release, suggesting that the 2-OH of Ins(1 ,4,5)P3 fails to interact significantly with the binding site of its receptor. However, modification remote from the crucial vicinal 4,s-bisphosphate can affect analogue efficacy in Ca2+ release.Many cell surface receptors activate the enzyme l-phosphatidylinositol-4,5-bisphosphate phosphodiesterase via Gproteins. This enzyme (EC 3.1.4.11) catalyses the hydrolysis of phosphatidylinositol 4,5-bisphosphate to produce the second messengers myo-inositol 1,4,5-trisphosphate [Ins-(1,4,S)P3] ( Fig. 1 ; all references to inositol refer to the myoisomer unless otherwise specified) and diacylglycerol [ 11.

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confidence: 99%

Modification at C2 of myo‐inositol 1,4,5‐trisphosphate produces inositol trisphosphates and tetrakisphosphates with potent biological activities

Wilcox

Safrany

Lampe

et al. 1994

European Journal of Biochemistry

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“…The residue of each compound was purified by ion-exchange chromatography on Q-Sepharose Fast Flow using a gradient of aqueous triethylammonium bicarbonate (TEAB) 0-1 M as eluent. The inositol 1,4,6-trisphosphates (6)(7)(8)(9)(10)(11) eluted between 55% and 75% 1 M TEAB and the appropriate fractions were pooled and the solvent was evaporated to give the trisphosphates as their triethylammonium salts. In all cases the final myo-inositol 1,4,6-trisphosphate compounds 6-11 were quantified by total phosphate assay using a modified Briggs test 27 in order to determine the amount of compound present.…”

Section: Resultsmentioning

confidence: 99%

First derivatives of myo-inositol 1,4,6-trisphosphate modified at positions 2 and 3: structural analogues of d-myo-inositol 1,4,5-trisphosphate

Horne

Mills

Potter

2004

Carbohydrate Research

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“…The 2-OH [which mimics the 6-OH of Ins(1,4,5)P 3 ] is reoriented to axial in 3,6)PS 3 and is therefore different from that in D-Ins(1,4,5)P 3 , whereas the OH group corresponding to the 3-OH of Ins(1,4,5)P 3 remains equatorial. From structure-activity studies, the 3-OH group of Ins(1,4,5)P 3 seems to have only a minor role in receptor recognition (Hirata et al, 1989;Seewald et al, 1990); thus, reorientation of the OH-group on the "pseudo" 3-position (actually the 2-position) of the inositol ring [as in Ins(1,4,6)PS 3 ] might not be expected to have a significant effect on Ins(1,4,5)P 3 binding. However, modification at the 6-OH group [as in Ins(1,3,6)PS 3 ] would be expected to reduce binding and activity (Polokoff et al, 1988;Safrany et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

myo-Inositol 1,4,6-Trisphosphorothioate andmyo-Inositol 1,3,6-Trisphosphorothioate: Partial Agonists with Very Low Intrinsic Activity at the Plateletmyo-Inositol 1,4,5-Trisphosphate Receptor

et al. 2000

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Racemic mixtures and enantiomerically pure D-isomers of both myo-inositol 1,3,6-trisphosphorothioate [Ins(1,3,6)PS(3)] and myo-inositol 1,4,6-trisphosphorothioate [Ins(1,4,6)PS(3)], prepared by total synthesis, were examined in Ca(2+) flux and binding assays. Both D-Ins(1,3,6)PS(3) and D-Ins(1,4,6)PS(3) were shown to be low intrinsic activity partial agonists at the platelet myo-inositol 1,4, 5-trisphosphate [Ins(1,4,5)P(3)] receptor, releasing less than 20% of the Ins(1,4,5)P(3)-sensitive Ca(2+) store. D-Ins(1,4,6)PS(3) displaced specifically bound [(3)H]Ins(1,4,5)P(3) from rat cerebellar membranes, although displacement was some 34-fold weaker than by D-Ins(1,4,5)P(3). D-Ins(1,4,6)PS(3) displaced [(3)H]Ins(1,4, 5)P(3) from cerebellar membranes with roughly twice the affinity of DL-Ins(1,4,6)PS(3) (IC(50) value = 1.4 +/- 0.35 microM compared with 2.15 +/- 0.13 microM), whereas D-Ins(1,3,6)PS(3) displaced [(3)H]Ins(1,4,5)P(3) with roughly twice the affinity of DL-Ins(1,3, 6)PS(3) (IC(50) value = 17.5 +/- 5.8 microM compared with 34 +/- 10 microM), confirming that the activity of both these phosphorothioates resides in their D-enantiomers. Increasing concentrations of either D-Ins(1,3,6)PS(3) or D-Ins(1,4,6)PS(3) were able to partially antagonize Ca(2+) release induced by submaximal concentrations of Ins(1,4,5)P(3), an inhibition that could be overcome by increasing the concentration of Ins(1,4,5)P(3), suggesting competition for binding at the Ins(1,4,5)P(3)-R. The only low-efficacy partial agonists at the Ins(1,4,5)P(3)-R discovered to date have been phosphorothioates; the novel D-Ins(1,3,6)PS(3) and D-Ins(1,4,6)PS(3) can now be added to this small group of analogs. However, D-Ins(1,4,6)PS(3) has a relatively high affinity for the Ins(1,4,5)P(3)-R but maintains the lowest efficacy of all the partial agonists thus far identified. As such, it may be a useful tool for pharmacological intervention in the polyphosphoinositide pathway and an important lead compound for the development of further Ins(1,4,5)P(3)-R antagonists.

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Synthesis of D-3-deoxy-myo-inositol 1,4,5-trisphosphate and its effect on Ca2+ release in NIH 3T3 cells

Cited by 24 publications

References 8 publications

Modification at C2 of myo‐inositol 1,4,5‐trisphosphate produces inositol trisphosphates and tetrakisphosphates with potent biological activities

Modification at C2 of myo‐inositol 1,4,5‐trisphosphate produces inositol trisphosphates and tetrakisphosphates with potent biological activities

First derivatives of myo-inositol 1,4,6-trisphosphate modified at positions 2 and 3: structural analogues of d-myo-inositol 1,4,5-trisphosphate

myo-Inositol 1,4,6-Trisphosphorothioate andmyo-Inositol 1,3,6-Trisphosphorothioate: Partial Agonists with Very Low Intrinsic Activity at the Plateletmyo-Inositol 1,4,5-Trisphosphate Receptor

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