Improved syntheses of inositol phospholipid analogues

Jones, Martin; Rana, Kishore K.; Ward, Jacob; Young, R. C.

doi:10.1016/s0040-4039(01)93785-2

Cited by 36 publications

(8 citation statements)

References 5 publications

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“…The camphanate derivative was then deacylated in methanolic sodium hydroxide. The less polar diastereoisomer was identified as being a derivative of d -1,2:4,5-di- O -isopropylidene- myo -inositol 22 , by virtue of its rotation, and close to the literature values. − The other, more polar diastereoisomeric camphanate was isolated by chromatography, then deacylated, as previously described, giving l -6- O - p -methoxybenzyl-1,2:4,5-di- O -isopropylidene- myo -inositol, and used for the synthesis of inositol triflate 11 (Scheme ).…”

Section: Resultssupporting

confidence: 53%

“…Key features include coupling of a chiral-protected myo -inositol diol derivative activated as its triflate 11 to the chiral-protected ribose derivative 12 . The chiral diol d -(−)-1,2:4,5-di- O -isopropylidene- myo -inositol 22 , − derived from the separable diastereoisomeric 3- O -camphanate derivative of its 6- O - p -methyoxybenzyl ether, was used to define the absolute configuration of 11 by comparison with the literature values. Subsequent elaboration of the coupled product after deprotection of the labile isopropylidene group and monobenzylation of the stannylene-mediated vicinal hydroxyl group with separation and identification of regioisomers afforded a suitably protected triol 17 .…”

Section: Discussionmentioning

confidence: 99%

“…[α] D = −23°, temperature = 21 °C, c = 0.50 in CH 3 CN, Lit. + 22° ( c = 1.08, MeCN) (for opposite enantiomer). Lit.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Resultssupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…δ H (400 MHz, CD 3 OD): 0.88 (6H, t, J ) 6.5 Hz, CH 3 ), 1. 25 (19)(20)(21)28), and 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,3triazole (1.07 g, 3.61 mmol) (29) was dissolved in dry pyridine (8.8 mL) and stirred under an atmosphere of nitrogen for 2 h. The mixture was partitioned between saturated aqueous sodium chloride solution (50 mL) and diethyl ether (150 mL) and separated, and the aqueous layer was extracted with diethyl ether (150 mL). The combined extracts were dried with magnesium sulfate, filtered, and evaporated to dryness in vacuo.…”

Section: Methodsmentioning

confidence: 99%

Orientation of the Headgroup of Phosphatidylinositol in a Model Biomembrane As Determined by Neutron Diffraction

et al. 1999

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Derivatives of the sodium salt of dimyristoylphosphatidylinositol (DMPI) have been synthesized specifically deuterated in the headgroup. A 50:50 (molar) mixture of DMPI with dimyristoylphosphatidylcholine (DMPC) hydrated to the level of 16 waters/lipid gives a biomembrane-like Lalpha phase at 50 degrees C. Comparison of the neutron diffraction scattering profiles for deuterated and undeuterated membranes allowed the depth of each deuterium (hydrogen) within the bilayer to be determined to +/-0.5 A. This gave the orientation of the inositol ring which lies more-or-less along the bilayer normal projecting directly out into the water. This orientation is similar to that of the sugar residue in glycolipids and confirms previous models for PI. On the assumption that the (P)O-DAG bond is more-or-less parallel to the bilayer normal, it is consistent with a roughly trans, trans, trans, gauche- conformation for the glyceryl-phosphate-inositol link. In the case of DMPI, it is the C4-hydroxy group which is most fully extended into the water layer, but when this is phosphorylated, the inositol ring turns over and tilts so that the C5-hydroxy group is now the one furthest extended into the water layer. Hence, at each stage in the pathway PI --> PI-4P --> PI-4,5-P2, it is the hydroxy position most exposed to the water which undergoes phosphorylation. Whereas the orientation of the inositol ring in DMPI can be seen simply as maximizing its hydration, the tilt of the ring in DMPI-4P cannot be explained in this way. It is suggested that it is due to an electrostatic interaction.

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“…Several chemical methods to synthesize PI have also been published (7)(8)(9)(10)(11)(12)(13). However, those methods have been rarely employed, most probably because they require considerable expertise in organic chemistry (e.g., 10,12), only saturated PI species can be prepared (13)(14)(15), or because the yield of PI is low and/or variable (see 14).…”

mentioning

confidence: 99%

Simple and rapid biochemical method to synthesize labeled or unlabeled phosphatidylinositol species

Hänninen

Batchu

Hokynar

et al. 2017

Journal of Lipid Research

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Phosphatidylinositol (PI) is the precursor of many important signaling molecules in eukaryotic cells and, most probably, PI also has important functions in cellular membranes. However, these functions are poorly understood, which is largely due to that ) only few PI species with specific acyl chains are available commercially and) there are no simple methods to synthesize such species. Here, we present a simple biochemical protocol to synthesize a variety of labeled or unlabeled PI species from corresponding commercially available phosphatidylcholines. The protocol can be carried out in a single vial in a two-step process which employs three enzymatic reactions mediated by ) commercial phospholipase D from, ) CDP-diacylglycerol synthase overexpressed in and ) PI synthase of ectopically expressed in The PI product is readily purified from the reaction mixture by liquid chromatography since does not contain endogenous PI or other coeluting lipids. The method allows one to synthesize and purify labeled or unlabeled PI species in 1 or 2 days.Typically, 40-60% of (unsaturated) PC was converted to PI albeit the final yield of PI was less (25-35%) due to losses upon purification.

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Improved syntheses of inositol phospholipid analogues

Cited by 36 publications

References 5 publications

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

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

Orientation of the Headgroup of Phosphatidylinositol in a Model Biomembrane As Determined by Neutron Diffraction

Simple and rapid biochemical method to synthesize labeled or unlabeled phosphatidylinositol species

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