Novel syntheses of Idraparinux, the anticoagulant pentasaccharide with indirect selective factor Xa inhibitory activity

Herczeg, Mihály; Mező, Erika; Lázár, László; Fekete, Anikó; Kövér, Katalin E.; Antus, Sándor; Borbás, Anikó

doi:10.1016/j.tet.2013.02.076

Cited by 18 publications

(16 citation statements)

References 32 publications

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“…Over the last years, we have developed several new methods for the synthesis of idraparinux 20 , 40 , 41 . The most efficient strategy involves a 3 + 2 coupling of a FGH trisaccharide acceptor and a DE disaccharide donor, and application of acetyl groups to mask the hydroxyls to be methylated and benzyl ethers to protect the hydroxyls to be sulfated in the final product 20 .…”

Section: Resultsmentioning

confidence: 99%

“…6 ). According to our previously established strategy, we planned the oxidation of the glucose precursor E into D-glucuronic acid at the pentasaccharide level 20 , 24 , 41 . Condensation reaction of the isopropylidene-containing trisaccharide acceptor 20 and donor 25 upon NIS-TMSOTf activation provided the needed pentasaccharide 26 together with its diol derivative 27 formed by partial loss of the acetal group under the acidic conditions of the coupling.…”

Section: Resultsmentioning

confidence: 99%

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Replacement of the L-iduronic acid unit of the anticoagulant pentasaccharide idraparinux by a 6-deoxy-L-talopyranose – Synthesis and conformational analysis

Demeter

Gyöngyösi

Bereczky

et al. 2018

Sci Rep

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One critical part of the synthesis of heparinoid anticoagulants is the creation of the L-iduronic acid building block featured with unique conformational plasticity which is crucial for the anticoagulant activity. Herein, we studied whether a much more easily synthesizable sugar, the 6-deoxy-L-talose, built in a heparinoid oligosaccharide, could show a similar conformational plasticity, thereby can be a potential substituent of the L-idose. Three pentasaccharides related to the synthetic anticoagulant pentasaccharide idraparinux were prepared, in which the L-iduronate was replaced by a 6-deoxy-L-talopyranoside unit. The talo-configured building block was formed by C4 epimerisation of the commercially available L-rhamnose with high efficacy at both the monosaccharide and the disaccharide level. The detailed conformational analysis of these new derivatives, differing only in their methylation pattern, was performed and the conformationally relevant NMR parameters, such as proton-proton coupling constants and interproton distances were compared to the corresponding ones measured in idraparinux. The lack of anticoagulant activity of these novel heparin analogues could be explained by the biologically not favorable 1C4 chair conformation of their 6-deoxy-L-talopyranoside residues.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Replacement of the L-iduronic acid unit of the anticoagulant pentasaccharide idraparinux by a 6-deoxy-L-talopyranose – Synthesis and conformational analysis

Demeter

Gyöngyösi

Bereczky

et al. 2018

Sci Rep

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“…The synthesis of the substituents 16 and 17 started from methyl 4,6-O-p-methoxybenzylidene-α-D-glucopyranoside 13. 25 Di-O-n-butylation of 13 followed by reductive opening of the 4,6-acetal ring 31,32 of the obtained 14 gave 15. Subsequent alkylation of the liberated 6-hydroxyl group with a propargyl tetraethyleneglycol derivative produced 16, conjugation of which to azido teicoplanin pseudoaglycon 18 20 by the copper catalyzed azide-alkyne dipolar cycloaddition click reaction 33,34 furnished compound 4.…”

Section: Resultsmentioning

confidence: 99%

Lipophilic teicoplanin pseudoaglycon derivatives are active against vancomycin- and teicoplanin-resistant enterococci

et al. 2017

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A selection of nine derivatives of teicoplanin pseudoaglycon were tested in vitro against clinical vancomycin-resistant Enterococcus strains possessing vanA, vanB or both genes. The bacteria were characterized by PCR for the identification of their resistance genes. The tested compounds contain lipoic acid, different carbohydrates and aryl groups as lipophilic moieties. About one-third of the teicoplanin-resistant strains were shown to be susceptible to one or more of the glycopeptide derivatives.

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“…[12][13][14][15] Some years ago we initiated a research project to prepare isosteric sulfonic acid analogues of the antithrombin binding pentasaccharide domain of heparin to access new anticoagulants. [6,[16][17][18][19][20][21][22] Recently, we demonstrated that the blood clotting inhibitory activity of the parent highly sulfated pentasaccharide could be improved by the replacement of the primary sulfate esters with a sodium sulfonatomethyl group. [19] Continuing on from this, we targeted the synthesis of further pentasaccharide analogues bearing the sulfonic acid moiety at secondary positions by using thioglycoside building blocks bearing a dynamics and DFT calculations.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of C‐2‐ and C‐3‐Sulfonatomethyl O‐ and S‐Glycosides by Horner–Wadsworth–Emmons Olefination

Eszenyi¹,

Mándi²,

Herczeg³

et al. 2016

Eur J Org Chem

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The applicability of the Horner–Wadsworth–Emmons olefination to the introduction of the sulfonatomethyl moiety at the 2‐ and 3‐positions of orthogonally protected O‐ and S‐glycosides has been studied. The conformational preferences and relative energies of the exo‐ and endocyclic alkenesulfonic acids obtained were analysed by high‐temperature molecular dynamics and DFT calculations. Thioglycosides bearing a sulfonatomethyl moiety at the secondary position have been prepared for the first time. Finally, the attempted synthesis of 2‐sulfonatomethyl glucoside by nucleophilic substitution reaction is also described.

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Novel syntheses of Idraparinux, the anticoagulant pentasaccharide with indirect selective factor Xa inhibitory activity

Cited by 18 publications

References 32 publications

Replacement of the L-iduronic acid unit of the anticoagulant pentasaccharide idraparinux by a 6-deoxy-L-talopyranose – Synthesis and conformational analysis

Replacement of the L-iduronic acid unit of the anticoagulant pentasaccharide idraparinux by a 6-deoxy-L-talopyranose – Synthesis and conformational analysis

Lipophilic teicoplanin pseudoaglycon derivatives are active against vancomycin- and teicoplanin-resistant enterococci

Synthesis of C‐2‐ and C‐3‐Sulfonatomethyl O‐ and S‐Glycosides by Horner–Wadsworth–Emmons Olefination

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