Synthesis of an Acyloxymethyl Prodrug of the Inositol Phosphate α-Trinositol

ABSTRACT

Acyloxymethylation of an acylated silver salt of α-trinositol gives, after deprotection, membrane permeable 1D-myo-inositol 1,2,6-tris(ethoxycarbonyloxymethyl sodium phosphate). The acyl groups, 3-(4,5-methylenedioxy-2-nitrophenyl)propanoyl, are cleaved by hydrogenolysis.     

NMR and X-Ray Diffraction Study of Some Inositol Derivatives 1

Abstract

We have determined the preferred conformers in solution by a detailed NMR analysis using COSY and HETCOR experiments of three inositol isomers: myo (1), scyllo (2) and epi (3) plus sixteen derivatives of myo-inositol: 1,2,3,4,5,6-hexa-O-acetyl-myo-inositol (4), 1,2,-O-isopropylidene-myo-inositol (5), 1,2:4,5-di-O-isopropylidene-myo-inositol (6), 3,4,5,6-tetra-O-acetyl-1,2-O-isopropylidene-myo-inositol (7), 3,4,5,6-tetra-O-acetyl-myo-inositol (8), 1,2-O-isopropylidene-3,6-di-O-tosyl-myo-inositol (9), 1,2-O-isopropylidene-3,4,6-tri-O-tosyl-myo-inositol (10), 1,2:4,5-di-O-isopropylidene-3-O-tosyl-myo-inositol (11), 3,6-di-O-benzyl, 1,2:4,5-di-O-isopropylidene-myo-inositol (12), 3,6-di-O-benzyl-1,2-O-isopropylidene-myo-inositol (13), 3,6-di-O-benzyl-myo-inositol (14), 1,2-O-cyclohexylidene-myo-inositol (15), 1,2:4,5-di-O-cyclohexylidene-myo-inositol (16), 1,2:5,6-di-O-cyclohexylidene-myo-inositol (17), 1,3,5-O-(orthoformate)-myo-inositol (18) and 2-benzyl-1,3,5-O-(orthoformate)-myo-inositol (19). The X-ray diffraction structure of compounds 2, 6-8, 18 and 19 are reported.

     

Formation of (±)-1,2-O-Ethylidene-myo-Inositol During the Reaction Between Triethyl Orthoformate and myo-Inositol in DMSO

Besides myo-inositol monoorthoformate (1), (±)-1,2-O-ethylidene-myo-inositol (2) was obtained as another product in the reaction between triethyl orthoformate and myo-inositol in DMSO catalyzed by acid under N₂     

Iodonium Ion-Mediated Mannosylations of Myo-Inositol : Synthesis of a Mycobacteria Phospholipid Fragment

Abstract

Iodonium ion-mediated glycosylation of 1-O-allyl-3,4,5-tri-O-benzyl-6-O-para-methoxybenzyl-D/L-myo-inositol by ethyl 2-O-benzoyl-3,4,6-tri-O-benzyl-l-thio-α-D-mannopyranoside gave, after removal of the para-methoxybenzyl group and column chromatography, an α/β-mixture of the individual diastereoisomeric disaccharides. Subsequent stereospecific glycosylation of the α(1-2) linked mannopyranosyl-D-myo-inositol enantiomorph by the same ethyl 1-thiomannopyranoside donor afforded, after debenzoylarion, benzylation and subsequent deallylation the partially benzylated 2,6-dimannopyranosyl-D-myo-inositol derivative, the HO-1 position of which was phosphorylated, via the H-phosphonate method, with 1,2-dipalmitoyl-sn-glycerol. Oxidation of the intermediate phosphonate diester, and subsequent hydrogenolysis of the O-benzyl groups, furnished the target compound 1-O-(1,2-dipalmitoyl-sn-glycero-3-phosphoryl)-2,6-di-O-α-D-mannopyranosyl-D-myo-inositol.     

Paosphorothioate Analogues of Inositol Phosphates

Abstract

Novel analogues of the intracellular second messenger D-myo-inositol 1,4,5-trisphosphate, which possess phosphorothioate groups in place of phosphate groups have been synthesized. They exhibit unusual biological properties which will be of considerable application in understanding the phosphoinositide cycle.     

Absolute Configuration of 4-α-D-Glucopyranosyl-myo-inositol,Enzymatic Transglycosylation Product

Abstract

The absolute configuration of 4-α-D-glucopyranosyl-myo-inositol, one of the enzymatic transglycosylation products from cyclodextrin to myo-inositol, was confirmed by chemical synthesis. The glycosylation was shown to proceed in a highly diastereoselective manner by HPLC analysis of the chemically synthesized racemic glycoside.     

Untersuchungen über die Biosynthese der Cyclite, 17. Mitt.: Bildung vond-bornesit und Dambonit inNerium oleander

Zusammenfassung Dambonit (1,3-Di-O-methyl-myo-inosit) entsteht inNerium oleander, wie durch Einbauversuche mit radioaktiv markiertemmyo-Inosit undd-Bornesit sowie durch Bestimmung der Zeitabhängigkeit der Bildung der Cyclite bei Assimilation von¹⁴CO₂ nachgewiesen wurde, ausmyo-Inosit überd-Bornesit als Zwischenprodukt. Neben Dambonit finden sich in der Cyclitfraktion vonN. oleander auchd-Bornesit,myo-Inosit sowiel-Leucanthemit.myo-Inosit unterliegt in der Pflanze-besonders im Winter-einem sehr intensiven Stoffwechsel, der zu nichtzyklischen Verbindungen führt.

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InNerium oleander dambonitol (1,3-Di-O-methyl-myo-inositol) is formed frommyo-inositol withd-bornesitol as intermediate, as could be shown with the help of incorporation experiments with radioactively labelledmyo-inositol andd-bornesitol and also by the determination of the time dependence of the formation of the cyclitols from¹⁴CO₂ in photoassimilation experiments. Besides dambonitol the cyclitol fraction ofN. oleander contains alsod-bornesitol,myo-inositol andl-leucanthemitol. Especially in wintermyo-inositol undergoes a very active catabolism in the plant which leads to the formation of non-cyclic compounds.

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H. Kindl undO. Hoffmann-Ostenhof, Mh. Chem.97, 1771 (1966).     

Untersuchungen über die Biosynthese der Cyclite, 22. Mitt.: Cyclite inChlorella fusca

Zusammenfassung Das Vorkommen von Cycliten inChlorella fusca wurde mit Hilfe der Methode der Photoassimilation in einer Atmosphäre von¹⁴CO₂ untersucht. Außer dem bereits als Bestandteil dieser Algenart bekanntenmyo-Inosit konnten auch andere Cyclite, nämlichd-chiro-Inosit, Mytilit, Laminit undl-Leucanthemit nachgewiesen werden. Einbauversuche mit markierten Vorstufen ergaben, daßmyo-Inosit höchstwahrscheinlich auf dem schon in vielen Organismen nachgewiesenen Weg ausd-Glucose entsteht undd-chiro-Inosit das Produkt einer direkten Epimerisierung vonmyo-Inosit ist. Hingegen besteht keine biogenetische Beziehung zwischenmyo-Inosit und den beiden C-Methylinositen Mytilit und Laminit; die Methylgruppe vonl-Methionin wird nicht in diese beiden Verbindungen eingebaut.

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Studies on the biosynthesis of the cyclitols, XXII: Cyclites in chlorella fusca

The occurrence of cyclitols inChlorella fusca has been studied, using the method of photoassimilation in an atmosphere of¹⁴CO₂. Besidesmyo-inositol which is known to be a constituent of this algal species, other cyclitols were detected, namelyd-chiro-inositol, mytilitol, laminitol, andl-leucanthemitol. Incorporation experiments with labelled precursors make it most probable thatmyo-inositol is formed fromd-glucose through a pathway already established in many organisms, whereasd-chiro-inositol is the product of a direct epimerization ofmyo-inositol. No biogenetic relation exists betweenmyo-inositol and the two C-methylinositols; the methyl group ofl-methionine is not incorporated into these compounds.

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21. Mitt.:E. Molinari undO. Hoffmann-Ostenhof,Z. physiol. Chem.349, 1797 (1968).     

A new sepharose derivative containing covalently boundmyo-inositol: Its structure and application

myo-Inositol was covalently bound on, an epoxy-activated sepharose. In order to elucidate the structure of the derivative of sepharose formed, in a model reactionmyo-inositol was coupled to propylene oxide, whereby two compounds were obtained. By NMR-spectroscopy,¹³C-resonancespectroscopy and gas chromatography substanceI could be characterized as a mixture of two isomers. Both are the product of a binding to the hydroxyl group on C-atom 2 ofmyo-inositol. The only difference seems to be the point of attachment to the side chain. SubstanceII, however, originates by substitution on an equitorial hydroxyl group. The application of this new affinity gel is reported.

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Ein neues Sepharose-Derivat mit kovalent gebundenem myo-Inosit: Struktur und Anwendung

Zusammenfassung myo-Inosit wurde an eine epoxy-aktivierte Sepharose kovalent gebunden. Zur Aufklärung der Struktur dieses Sepharosederivats wurde in einer Modellreaktionmyo-Inosit an Propylenoxid gekoppelt, wobei zwei Substanzen erhalten wurden. Durch NMR-Spektren,¹³C-Resonanzspektren und Gaschromatographie konnte SubstanzI als Gemisch zweier Isomerer charakterisiert werden. Beide sind durch Derivatisierung, am C-Atom 2 des Inosits entstanden, sie unterscheiden sich nur im Ort der Bindung an der Seitenkette. Bei SubstanzII ist hingegen die Substitution an einem äquatorialen O-Atom eingetreten.Es wird über die Anwendung des neuen Affinitätsgels berichtet.

     

Total synthesis of a fully lipidated form of phosphatidyl-myo-inositol dimannoside (PIM-2) of Mycobacterium tuberculosis

Using an orthogonal protecting group approach to resolve racemic myo-inositol directly as its d-mannoside, we report a [2+n]-glycan/phosphatidylation strategy to assemble a bis-palmityl, tuberculostearyl form of phosphatidyl-myo-inositol dimannoside (PIM-2).     

Total Synthesis of (+)- and (−)-Ononitol

Abstract

A practical, five-step synthetic sequence for conversion of myo-inositol into enantiomerically pure (+)- and (?)-ononitols in 17% and 18% overall yield, respectively, has been developed.     

Syntheses of O-(2-Acetamido-2-Deoxy-α-D-Galactopyranosyl)-Myo-Inositols

ABSTRACT

The structure of an O-(2-acetamido-2-deoxy-α-D-galactopyranosyl)-myo-inositol isolated from human pregnancy urine has previously been identified as that of 1-O-(2-acetamido-2-deoxy-α-D-galactopyranosyl)-myo-inositol. In order to ascertain the absolute configuration in the inositol part of the compound, the 1D- and 1L- isomers were synthesised. Since none of these two stereoisomers corresponded to the natural product, the corresponding 2-O-, the mixture of the two 1DL-4-O-, and 5-O- isomers were also synthesised. None of these gave ¹H NMR spectra corresponding to the natural product, the structure of which therefore remains unresolved.     

Synthesis of Methyl (Methyl D-and L-Idopyranosid)Uronates from myo-Inositol

Abstract

Methyl (methyl α-D-(9a), α-(9b), β-D-(10a), and β-L-(10b) idopyranosid)uronates were synthesized from myo-inositol. Baeyer-Villiger oxidation of the optically resolved inosose derivatives (3a and 3b) proceeded regioselectively to afford 4a and 4b in high yields, respectively. Ring-opening of the 7-membered hemiacetal-lactones (4a and 4b) with acid and subsequent deprotection gave the title compounds.     

Untersuchungen über die Biosynthese der Cyclite, 16. Mitt.: Versuche über die Bildung und den Stoffwechsel vond-Bornesit in Boraginaceae und Leguminosae

Zusammenfassung Einbauversuche mit radioaktiv markiertemmyo-Inosit anBorago officinalis undMyosotis caucasica (Boraginaceae) sowie anLathyrus odoratus undMedicago sativa (Leguminosae) machen es sehr wahrscheinlich, daßd-Bornesit durch direkte Methylierung ausmyo-Inosit entsteht. Im Winter läßt sich nur eine relativ geringe Überführung vonmyo-Inosit ind-Bornesit nachweisen, hingegen werden beide Substanzen schnell zu nichtcyclischen Verbindungen abgebaut. Im Frühjahr wirdmyo-Inosit schnell zud-Bornesit methyliert, während der Abbau beider Cyclite anscheinend langsamer erfolgt. In allen genannten Pflanzen konnten neben größeren Mengen vond-Bornesit auchmyo-Inosit undl-Leucanthemit nachgewiesen werden.

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Incorporation experiments with radioactively labelledmyo-inositol inBorago officinalis andMyosotis caucasica (Boraginaceae) and inLathyrus odoratus andMedicago sativa (Leguminosae) make it very probable thatd-bornesitol is formed through direct methylation ofmyo-inositol. In winter the transformation ofmyo-inositol tod-bornesitol is relatively slow, whereas both substances are rapidly degraded to non-cyclic compounds. In spring the methylation ofmyo-inositol tod-bornesitol proceeds quickly; at this time the degradation seems to be much slower than in winter. It could be shown that besides higher amounts ofd-bornesitol all the named plants also containmyo-inositol andl-leucanthemitol.

     

Synthesis and Biological Evaluation of (2-Hydroxyethyl) 2-Deoxy-α-D-Threo-Pyranoside 3,4,2′-Trisphosphate,A Mimic of the Second Messenger Inositol 1,4,5-Trisphosphate

ABSTRACT

(2-Hydroxyethyl) 2-deoxy-α-D-threo-pentopyranoside 3,4,2′-trisphosphate (3) has been prepared starting from allyl-α-D-xylopyranoside. The suitably protected 2-deoxy intermediate obtained by judicious selective protection and deprotection has been phosphorylated using the phosphoramidite methodology. Final deprotection gave the expected analogue of myo-inositol 1,4,5-trisphosphate.     

Die Überführung vonmyo-Inosit in chinoide Substanzen inPseudomonas beijerinckii, 1. Mitt.: Über einemyo-Inosit-Dehydrogenase ausPseudomonas beijerinckii

Zusammenfassung Ein konstitutives Enzym mit der Spezifität einermyo-Inosit-Dehydrogenase (myo-Inosit: NAD-Oxydoreductase, ES 1.1.1.18) wurde ausPseudomonas beijerinckii isoliert, etwa 550fach angereichert und in seinen Eigenschaften charakterisiert.

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Transformation of myo-inositol to quinoid substances in pseudomonas beijerinckii, I: On a myo-inositol dehydrogenase of pseudomonas beijerinckii

A constitutive enzyme showing the specificity of amyo-inositol dehydrogenase (myo-inositol: NAD oxidoreductase, EC 1.1.1.18) has been isolated fromPseudomonas beijerinckii. It was concentrated to 550fold activity; its properties were determined.

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Mit 3 Abbildungen     

Development of a microwave-assisted extraction method for the recovery of bioactive inositols from lettuce (Lactuca sativa) byproducts

A microwave-assisted extraction (MAE) method was developed for the extraction of bioactive inositols (D-chiro- and myo-inositols) from lettuce (Lactuca sativa) leaves as a strategy for the revalorization of these agrofood residues. Gas chromatography-mass spectrometry was selected for the simultaneous determination of inositols and sugars (glucose, fructose, and sucrose) in these samples. A Box–Behnken experimental design was used to maximize the extraction of inositols based on the results of single factor tests. Optimal conditions of the extraction process were as follows: liquid-to-solid ratio of 100:1 v/w, 40°C, 30 min extraction time, 20:80 ethanol:water (v/v), and one extraction cycle. When compared with conventional solid-liquid extraction (SLE), MAE was found to be more effective for the extraction of target bioactive carbohydrates (MAE 5.42 mg/g dry sample versus SLE 4.01 mg/g dry sample). Then, MAE methodology was applied to the extraction of inositols from L. sativa leaves of different varieties (var. longifolia, var. capitata and var. crispa). D-chiro- and myo-inositol contents varied between 0.57–7.15 and 0.83–3.48 mg/g dry sample, respectively. Interfering sugars were removed from the extracts using a biotechnological procedure based on the use of Saccharomyces cerevisiae for 24 h. The developed methodology was a good alternative to classical procedures to obtain extracts enriched in inositols from lettuce residues, which could be of interest for the agrofood industry.     

Efficient purification and complete NMR characterization of galactinol,sucrose, raffinose,and stachyose isolated from Pinus halepensis (Aleppo pine) seeds using acetylation procedure

The use of precipitation followed by acetylation procedures and preparative TLC purification allowed a facile isolation of four carbohydrates from the methanol extract of Pinus halepensis seeds. The isolated oligosaccharides exhibited high degree of purity. They were identified as α-D-galactosyl-(1→1)-myo-inositol nonaacetate (1), α-D-glucosyl-(1→2)-β-D-fructosyl octaacetate (2), α-D-galactosyl-(1→6)-α-D-glucosyl-(1→2)-β-D-frutosyl undecaacetate (3), and α-D-galactosyl-(1→6)-α-D-galactosyl-(1→6)-α-D-glucosyl-(1→2)-β-D-frutosyl tetradecaacetate (4) and were isolated for the first time from this plant. The ¹H and ¹³C NMR assignments for compounds 2, 3, and 4 were detailed herein for the first time.     

Synthesis of partially bio-based triepoxides from naturally occurring myo-inositol and their polyadditions

Partially bio-based triepoxides, 1,3,5-tri-O-methyl-2,4,6-tri-O-(oxiran-2-yl-methyl)-myo-inositol ( 4 ) and 2,4,6-tri-O-(oxiran-2-yl-methyl)-myo-inositol 1,3,5-orthoacetate ( 5 ), were synthesized from naturally occurring myo-inositol. These two triepoxides differ from each other in terms of rigidity of the core structure; while the former triepoxide has a more flexible cyclohexane core, the latter has a highly rigid adamantane-like orthoester core. Triepoxide 5 readily reacted with nucleophilic monomers such as diamines, dithiol, and trithiol to yield networked polymers. The glass transition temperatures (T_gs) of these polymers were higher than those of comparable networked polymers obtained by the polyaddition of triepoxide 4 with the same nucleophilic monomers, implying that the rigidity of the orthoester moiety contributed to the efficient restriction of the polymer chain in the synthesized networked polymers.     

Stereoselective enzymatic synthesis of monoglucosyl-myo-inositols with in vivo anti-inflammatory activity

The monoglucosyl-inositols α-d-glucopyranosyl-(1→4)-4d-myo-inositol 3 and α-d-glucopyranosyl-(1→1)-1d-myo-inositol 4 were synthesized by a combined enzymatic transglucosylation and hydrolysis strategy, using cyclodextrin glucosyl transferase (CGTase) from Thermoanaerobacter sp., followed by hydrolysis with Aspergillus niger glucoamylase. The glucosides were separated by preparative HPLC and fully characterized by extensive 1D and 2D NMR studies. The structure of the regioisomer 4 was confirmed by X-ray crystallography of its perbenzoylated derivative 4a. Both isomers demonstrated in vivo anti-inflammatory activity at comparative levels to corticosterone on mouse ear oedema induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) and in rat hind paw oedema induced by carrageenan.