Inositol Derivatives Research Articles

Structural analysis of 1 l- chiro-inositol diester from Taraxacumudum

1 l-1,5-Di- O- p-hydroxyphenylacetyl- chiro-inositol was isolated from the leaves of Taraxacum udum, along with seven other secondary metabolites. Identification of the inositol derivative, based on extensive spectroscopic analyses ( 1H, 13C and 2D NMR) in two solvents, allowed the correction of previously published data and conformational studies. This is the second report on the presence of inositol esters with p-hydroxyphenylacetic acid in plants.

Relative reactivity of hydroxyl groups in inositol derivatives: role of metal ion chelation

O-Alkylation of myo-inositol derivatives containing more than one hydroxyl group via their alkali metal alkoxides (sodium or lithium) preferentially occurs at a hydroxyl group having a vicinal cis-oxygen atom. In general the observed selectivity is relatively higher for lithium alkoxides than for the corresponding sodium alkoxide. The observed regioselectivity is also dependent on other factors such as the solvent and reaction temperature. A perusal of the results presented in this article as well as those available in the literature suggests that chelation of metal ions by inositol derivatives plays a significant role in the observed regioselectivity. Steric factors associated with the axial or equatorial disposition of the reacting hydroxyl groups do not contribute much to the outcome of these O-alkylation reactions. These results could serve as guidelines in planning synthetic strategies involving other carbohydrates and their derivatives.

Plant phospholipid signaling: “in a nutshell”

Since the discovery of the phosphoinositide/phospholipase C (PI/PLC) system in animal systems, we know that phospholipids are much more then just structural components of biological membranes. In the beginning, this idea was fairly straightforward. Receptor stimulation activates PLC, which hydrolyses phosphatidylinositol4,5-bisphosphate [PtdIns(4,5)P2] into two second messengers: inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DG). While InsP3 difuses into the cytosol and triggers the release of calcium from an internal store via ligand-gated calcium channels, DG remains in the membrane where it recruits and activates members of the PKC family. The increase in calcium, together with the change in phosphorylation status, (in)activates a variety of protein targets, leading to a massive reprogramming, allowing the cell to appropriately respond to the extracellular stimulus. Later, it became obvious that not just PLC, but a variety of other phospholipid-metabolizing enzymes were activated, including phospholipase A, phospholipase D, and PI 3-kinase. More recently, it has become apparent that PtdIns4P and PtdIns(4,5)P2 are not just signal precursors but can also function as signaling molecules themselves. While plants contain most of the components described above, and evidence for their role in cell signaling is progressively increasing, major differences between plants and the mammalian paradigms exist. Below, these are described "in a nutshell."

Stereoselective Synthesis of Bishomo-inositols as Glycosidase Inhibitors

For the synthesis of various bishomo-inositol derivatives, 1,3,3a,7a-tetrahydro-2-benzofuran was used as the key compound. For further functionalization of the diene unit, the diene was subjected to photooxygenation, epoxidation, and cis-hydroxylation reactions. The endoperoxide linkage was cleaved by thiourea. The remaining double bond was subjected to epoxidation and cis-hydroxylation reactions. The epoxide rings and tetrahydrofuran rings formed were opened by acid-catalyzed reaction with sulfamic acid. The combination of these reactions resulted in the formation of various new inositol derivatives such as bishomo-chiro-inositol, bishomo-myo-inositol, and two isomeric bishomo-allo-inositols.

Inositol angelates from the whole herb of Inula cappa

A new inositol derivative, cis-1,2,3,5-trans-4,6-inositol-2,3,6-triangelate(1) along with the known l-inositol-1,2,3,5-tetra angelate(2), was isolated from the ethanolic extract of the whole plant Inula cappa and identified on the spectroscopic analysis.

Inositol derivatives: evolution and functions

Current research on inositols mainly focuses on myo-inositol (Ins) derivatives in eukaryotic cells, and in particular on the many roles of Ins phospholipids and polyphosphorylated Ins derivatives. However, inositols and their derivatives are more versatile than this--they have acquired diverse functions over the course of evolution. Given the central involvement of primordial bacteria and archaea in the emergence of eukaryotes, what is the status of inositol derivatives in these groups of organisms, and how might inositol, inositol lipids and inositol phosphates have become ubiquitous constituents of eukaryotes? And how, later, might the multifarious functions of inositol derivatives have emerged during eukaryote diversification?

Rat L6 myotubes as an in vitro model system to study GLUT4-dependent glucose uptake stimulated by inositol derivatives

Some of inositol derivatives have been reported to help the action of insulin stimulating glucose uptake in skeletal muscle cells. Rat L6 myotubes were employed in an attempt to develop an in vitro model system for investigation of the possible insulin-like effect of eight inositol derivatives, namely allo-inositol, D: -chiro-inositol L: -chiro-inositol, epi-inositol, muco-inositol, myo-inositol, scyllo-inositol and D: -pinitol. At a higher concentration of 1 mM seven inositol derivatives other than myo-inositol were able to stimulate glucose uptake, while at 0.1 mM only D: -chiro-inositol, L: -chiro-inositol, epi-inositol and muco-inositol could induce glucose uptake, indicating their significant insulin-mimetic activity. Immunoblot analyses revealed that at least D: -chiro-inositol, L: -chiro-inositol, epi-inositol, muco-inositol and D: -pinitol were able to induce translocation of glucose transporter 4 (GLUT4) to plasma membrane not only in L6 myotubes but also in skeletal muscles of rats ex vivo. These results demonstrated that L6 myotubes appeared efficient as an in vitro system to identify inositol derivatives exerting an insulin-like effect on muscle cells depending on the induced translocation of GLUT4.

Biology‐Enabling Inositol Phosphates, Phosphatidylinositol Phosphates and Derivatives

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Divergent Synthesis of All Possible Optically Active Regioisomers of Myo‐Inositol Mono‐ and Bisphosphates

All possible optically active regioisomers of myo‐inositol mono‐ and bisphosphates were synthesized using inositol derivatives suitably protected with various protecting groups (IRns) as key intermediates. A series of procedures including Novozym 435 catalyzed enzymatic resolution of (3aR,4S,7S,7aR)‐rel‐3a,4,7,7a‐tetrahydro‐2,2‐dimethyl‐1,3‐benzodioxole‐4,7‐diol diacetate, several protection and deprotection reactions, and acyl migration afforded two enantiomeric pairs of IR5 and six enantiomeric pairs of IR4. Phosphorylation of these key intermediates by the phosphitylation and oxidation procedure gave the target products after removal of the protecting groups.

Probing the Promiscuous Active Site of myo-Inositol Dehydrogenase Using Synthetic Substrates, Homology Modeling, and Active Site Modification

The active site of myo-inositol dehydrogenase (IDH, EC 1.1.1.18) from Bacillus subtilis recognizes a variety of mono- and disaccharides, as well as 1l-4-O-substituted inositol derivatives. It catalyzes the NAD+-dependent oxidation of the axial alcohol of these substrates with comparable kinetic constants. We have found that 4-O-p-toluenesulfonyl-myo-inositol does not act as a substrate for IDH, in contrast to structurally similar compounds such as those bearing substituted benzyl substituents in the same position. X-ray crystallographic analysis of 4-O-p-toluenesulfonyl-myo-inositol and 4-O-(2-naphthyl)methyl-myo-inositol, which is a substrate for IDH, shows a distinct difference in the preferred conformation of the aryl substituent. Conformational analysis of known substrates of IDH suggests that this conformational difference may account for the difference in reactivity of 4-O-p-toluenesulfonyl-myo-inositol in the presence of IDH. A sequence alignment of IDH with the homologous glucose-fructose oxidoreductase allowed the construction of an homology model of inositol dehydrogenase, to which NADH and 4-O-benzyl-scyllo-inosose were docked and the active site energy minimized. The active site model is consistent with all experimental results and suggests that a conserved tyrosine-glycine-tyrosine motif forms the hydrophobic pocket adjoining the site of inositol recognition. Y233F and Y235F retain activity, while Y233R and Y235R do not. A histidine-aspartate pair, H176 and D172, are proposed to act as a dyad in which H176 is the active site acid/base. The enzyme is inactivated by diethyl pyrocarbonate, and the mutants H176A and D172N show a marked loss of activity. Kinetic isotope effect experiments with D172N indicate that chemistry is rate-determining for this mutant.

Evolution of the diverse biological roles of inositols

Several of the nine hexahydroxycylohexanes (inositols) have functions in Biology, with myo-inositol (Ins) in most of the starring roles; and Ins polyphosphates are amongst the most abundant organic phosphate constituents on Earth. Many Archaea make Ins and use it as a component of diphytanyl membrane phospholipids and the thermoprotective solute di-L-Ins-1,1'-phosphate. Few bacteria make Ins or use it, other than as a carbon source. Those that do include hyperthermophilic Thermotogales (which also employ di-L-Ins-1,1'-phosphate) and actinomycetes such as Mycobacterium spp. (which use mycothiol, an inositol-containing thiol, as an intracellular redox reagent and have characteristic phosphatidylinositol-linked surface oligosaccharides). Bacteria acquired their Ins3P synthases by lateral gene transfer from Archaea. Many eukaryotes, including stressed plants, insects, deep-sea animals and kidney tubule cells, adapt to environmental variation by making or accumulating diverse inositol derivatives as 'compatible' solutes. Eukaryotes use phosphatidylinositol derivatives for numerous roles in cell signalling and regulation and in protein anchoring at the cell surface. Remarkably, the diradylglycerol cores of archaeal and eukaryote/bacterial glycerophospholipids have mirror image configurations: sn-2,3 and sn-1,2 respectively. Multicellular animals and amoebozoans exhibit the greatest variety of functions for PtdIns derivatives, including the use of PtdIns(3,4,5)P3 as a signal. Evolutionarily, it seems likely that (i) early archaeons first made myo-inositol approx. 3500 Ma (million years) ago; (ii) archeons brought inositol derivatives into early eukaryotes (approx. 2000 Ma?); (iii) soon thereafter, eukaryotes established ubiquitous functions for phosphoinositides in membrane trafficking and Ins polyphosphate synthesis; and (iv) since approx. 1000 Ma, further waves of functional diversification in amoebozoans and metazoans have introduced Ins(1,4,5)P3 receptor Ca2+ channels and the messenger role of PtdIns(3,4,5)P3.

Evolution of the diverse biological roles of inositols

Several of the nine hexahydroxycylohexanes (inositols) have functions in Biology, with myo-inositol (Ins) in most of the starring roles; and Ins polyphosphates are amongst the most abundant organic phosphate constituents on Earth. Many Archaea make Ins and use it as a component of diphytanyl membrane phospholipids and the thermoprotective solute di-L-Ins-1,1′-phosphate. Few bacteria make Ins or use it, other than as a carbon source. Those that do include hyperthermophilic Thermotogales (which also employ di-l-Ins-1,1′-phosphate) and actinomycetes such as Mycobacterium spp. (which use mycothiol, an inositol-containing thiol, as an intracellular redox reagent and have characteristic phosphatidylinositol-linked surface oligosaccharides). Bacteria acquired their Ins3P synthases by lateral gene transfer from Archaea. Many eukaryotes, including stressed plants, insects, deep-sea animals and kidney tubule cells, adapt to environmental variation by making or accumulating diverse inositol derivatives as ‘compatible’ solutes. Eukaryotes use phosphatidylinositol derivatives for numerous roles in cell signalling and regulation and in protein anchoring at the cell surface. Remarkably, the diradylglycerol cores of archaeal and eukaryote/bacterial glycerophospholipids have mirror image configurations: sn-2,3 and sn-1,2 respectively. Multicellular animals and amoebozoans exhibit the greatest variety of functions for PtdIns derivatives, including the use of PtdIns(3,4,5)P3 as a signal. Evolutionarily, it seems likely that (i) early archaeons first made myo-inositol approx. 3500 Ma (million years) ago; (ii) archeons brought inositol derivatives into early eukaryotes (approx. 2000 Ma?); (iii) soon thereafter, eukaryotes established ubiquitous functions for phosphoinositides in membrane trafficking and Ins polyphosphate synthesis; and (iv) since approx. 1000 Ma, further waves of functional diversification in amoebozoans and metazoans have introduced Ins(1,4,5)P3 receptor Ca2+ channels and the messenger role of PtdIns(3,4,5)P3.

α-Pinene-type monoterpenes and other constituents from Artemisia suksdorfii

Two α-pinene-type monoterpenes, 7-hydroxymyrtenol ( 1) and 7-hydroxymyrtenal ( 2), a inositol derivative, (+)-quebrachitol ( 3) and two p-menthene triols ( 4 and 5), in addition to two known compounds were isolated from the aerial parts of Artemisia suksdorfii. The structures of the isolated compounds were established by analysis of spectroscopic data (IR, HR-MS, 1H and 13C NMR), including high-field 2D NMR techniques ( 1H– 1H COSY, HMQC, HMBC and NOE) and in case of 3 was confirmed by X-ray analysis.

Tocopheryl phosphate, a novel natural form of vitamin E: in vitro and in vivo studies

Tocopheryl phosphate (TP) has been found to be present in a number of tissues as well as foodstuffs. When added to smooth muscle cells in vitro, TP exhibits higher growth inhibition potency relatively to alpha tocopherol (T). The same stronger inhibition is observed in CD36 expression. TP inhibits PMA induced superoxide production in macrophages at lower concentrations than AT. If AT is incubated with digitonin permeabilized smooth muscle cells or macrophages, addition of [32P]ATP results in the synthesis of [32P]-tocopherol. Tocopheryl phosphate has been shown to be hydrolyzed by alkaline phosphatase at a rate of 1/1000 relative to p-nitro-phenyl-phosphate. In a rabbit model of atherosclerosis (2% cholesterol in the diet) TP (0.3–1.33 mg/kg diet) diminishes the amount of the atherosclerotic plaque of more than 60%, while tocopheryl acetate was only about 20% protective. In plasma of animals supplemented with tocopheryl acetate, tocopherol concentration was highly. In animals supplemented with tocopheryl phosphate plasma concentration of tocopherol was low while that of tocopheryl phosphate was high. The hypothesis will be discussed that tocopherol acts at the cellular level after phosphorylation to tocopheryl-phosphate. Such a reaction implies the existence of a kinase and of a phosphatase to dephosphorylate it. A possible interference of T phosphorylation with the phosphorylation of inositol derivatives and a possible molecular mechanism of TP similar to that of phosphatidylinositol phosphates will be also considered.

Non-classical hydrogen bonding involving bound diazides in an inositol derivative

The inositol derivative 1d-1,2-diazido-1,2-dide­oxy-3,4,5,6-tetra-O-benzyl-myo-inositol diethyl ether 0.6-solvate, C34H34N6O4·0.6C4H10O, packs with weak and unusual C—H⋯N,O hydrogen bonds and C—H⋯π inter­actions.

Biological Activity and Chemical Prospects of Inositol Derivatives

AbstractFor Abstract see ChemInform Abstract in Full Text.

Flexible Stereo‐ and Regioselective Synthesis of myo‐Inositol Phosphates(Part 2): Via Nonsymmetrical Conduritol B Derivatives

AbstractA practical route is described for the preparation of myo‐inositol phosphates. Optically pure compounds can be prepared, in both forms, from p‐benzoquinone by enzymatic resolution of a diacetoxyconduritol key intermediate. Monosubstituted inositol derivatives can be obtained by breaking the C2 symmetry of conduritol B derivatives. A wide variety of myo‐inositol phosphates can be synthesized by combining the previously reported symmetrical approach with this new nonsymmetrical approach. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Design and synthesis of glycosidase inhibitor 5-amino-1,2,3,4-cyclohexanetetrol derivatives from (−)- vibo-quercitol

In continuation of development of bioactive inositol derivatives, a 1- O-methyl derivative of 5-amino-5-deoxy- l- talo-quercitol was designed and synthesized as an analogue of the strong α-fucosidase inhibitor, 5a-carba-α- l-fucopyranosylamine, the methyl branch being replaced with methoxyl, and demonstrated to be a moderate α-fucosidase inhibitor. The present approach provides a possible route to apply alkyl ethers of aminodeoxyinositols as hexopyranose mimics of biological interest.

Resolution of synthetically useful myo-inositol derivatives using the chiral auxiliary O-acetylmandelic acid

Efficient methods for the resolution of various myo-inositol derivatives have been developed using O-acetylmandelic acid (OAM) as the chiral auxiliary. Various methods of introduction of the chiral auxiliary have been compared. DCC mediated coupling between the inositol derivative and O-acetylmandelic acid resulted in substantial racemization even at 0 °C; while acylation with O-acetylmandeloyl chloride in the presence of pyridine gave the diastereomers without any racemization of the chiral auxiliary. The advantage of using OAM as a chiral auxiliary is that the absolute configuration of the resolved diastereomers can be determined by analyzing the 1H NMR chemical shifts of various protons. The diastereomeric separation has been achieved either by fractional crystallization or column chromatography. The enantiomers of inositol derivatives could be obtained by the removal of chiral auxiliaries. By employing the known selective protection–deprotection strategies, various derivatives in optically active form could be synthesized.

Stereoselective oxidation of protected inositol derivatives catalyzed by inositol dehydrogenase from Bacillus subtilis

Inositol dehydrogenase (EC 1.1.1.18) from Bacillus subtilis is shown to have a nonpolar cavity adjacent to the active site, allowing racemic protected inositol derivatives such as 4-O-benzyl-myo-inositol to be recognized with very high apparent stereoselectivity.