Enzymatic synthesis of new C-6-acylated derivatives of NAG-thiazoline and evaluation of their inhibitor activities towards fungal β-N-acetylhexosaminidase

Krejzová, Jana; Šimon, Petr; Vavříková, Eva; Slámová, Kristýna; Riva, Sergio; Spiwok, Vojtěch; Křen, Vladimı́r

doi:10.1016/j.molcatb.2012.10.016

Cited by 13 publications

(15 citation statements)

References 35 publications

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“…We can conclude that both tested inhibitors are highly selective for the GH84 glycosidases while the C-6-azido derivative 2 remains less effective than the parent compound 1 . Similar result has been shown previously with other structurally modified NAG-thiazolines [5,6,8] with the only exception of the potential Alzheimer’s therapeutic thiamet-G [3]. Thus, new pathways are still to be found that lead to derivatives conquering the inhibition potency of 1 .…”

Section: Resultssupporting

confidence: 87%

“…The parent compound NAG-thiazoline ( 1 ) is a well established competitive mechanism-based inhibitor of the GH20 β- N -acetylhexosaminidases and GH84 β- N -acetylglucosaminidases [1,5]. Based on its structure, a number of analogues were designed and tested as β- N -acetylhexosaminidase inhibitors, including various N -acyl-derivatives [3,5,6] and the C-6-acylated derivatives [8]. Thus, the prepared monomeric ( 2 – 8 ) and dimeric ( 9 , 10 ) derivatives of NAG-thiazoline bearing the azido or triazole moiety at C-6 were designed as potential competitive inhibitors of GlcNAc-processing enzymes from the families 20 and 84 of glycoside hydrolases.…”

Section: Resultsmentioning

confidence: 99%

“…A kinetic study with NAG-thiazoline and a series of its derivatives with extended N -acyl moieties demonstrated that both types of human β- N -acetylhexosaminidases (GH20 and 84) are inhibited by thiazoline 1 in a very similar way (K I 70 nM), while the N -acyl-modified analogues of 1 are generally weaker inhibitors displaying high selectivity towards O -GlcNAcase [5]. Several more series of various derivatives based on the NAG-thiazoline scaffold have been introduced, e.g., a set of NAG-thiazolines bearing substituents of the thiazoline ring [6], C-1 homologated thiazolines [7], and a series of C-6-acylated analogues of NAG-thiazoline [8]; however, none of those derivatives ever reached the inhibition potency of the parent compound 1 . Detailed kinetic and structural studies of O -GlcNAcases have enabled the design of the so far most potent and selective NAG-thiazoline-based inhibitor of human O -GlcNAcase called thiamet-G, which displays a 37,000-fold higher selectivity for O -GlcNAcase (K I 21 nM) over lysosomal β- N -acetylhexosaminidase (K I 750 μM).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives

et al. 2014

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NAG-thiazoline is a strong competitive inhibitor of GH20 β-N-acetylhexosaminidases and GH84 β-N-acetylglucosaminidases. Here, we focused on the design, synthesis and inhibition potency of a series of new derivatives of NAG-thiazoline modified at the C-6 position. Dimerization of NAG-thiazoline via C-6 attached triazole linkers prepared by click chemistry was employed to make use of multivalency in the inhibition. Novel compounds were tested as potential inhibitors of β-N-acetylhexosaminidases from Talaromyces flavus, Streptomyces plicatus (both GH20) and β-N-acetylglucosaminidases OPEN ACCESSMolecules 2014, 19 3472 from Bacteroides thetaiotaomicron and humans (both GH84). From the set of newly prepared NAG-thiazoline derivatives, only C-6-azido-NAG-thiazoline displayed inhibition activity towards these enzymes; C-6 triazole-substituted NAG-thiazolines lacked inhibition activity against the enzymes used. Docking of C-6-azido-NAG-thiazoline into the active site of the tested enzymes was performed. Moreover, a stability study with GlcNActhiazoline confirmed its decomposition at pH < 6 yielding 2-acetamido-2-deoxy-1-thio-α/β-D-glucopyranoses, which presumably dimerize oxidatively into S-S linked dimers; decomposition products of NAG-thiazoline are void of inhibitory activity.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives

et al. 2014

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“…C 6 -dicarboxylic acid diesters derivatives of the thiazoline of N -acetylglucosamine (NAG-thiazoline, 10a , b , Fig. 2 ) were prepared and their inhibitor activities towards fungal β- N -acetylhexosaminidase evaluated [ 28 ].…”

Section: Reviewmentioning

confidence: 99%

“…The obvious hypothesis related to the synthesis of these compounds was that a dimer should be more bioactive than a monomer, but this was not always the case [ 28 – 29 ].…”

Section: Reviewmentioning

confidence: 99%

Dicarboxylic esters: Useful tools for the biocatalyzed synthesis of hybrid compounds and polymers

Bassanini¹,

Hult²,

Riva³

2015

Beilstein J. Org. Chem.

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Tetrazine‐Triggered Release of Carboxylic‐Acid‐Containing Molecules for Activation of an Anti‐inflammatory Drug

et al. 2019

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In addition to its use for the study of biomolecules in living systems, bioorthogonal chemistry has emerged as ap romising strategyt oe nable protein or drug activation in as patially and temporally controlled manner.T his study demonstrates the application of ab ioorthogonal inverse electron-demand Diels-Alder (iEDDA) reaction to cleave trans-cyclooctene (TCO) and vinyl protecting groups from carboxylic acid-containing molecules. The tetrazine-mediated decaging reactionp roceeded under biocompatiblec onditions with fast reaction kinetics (< 2min). The anti-inflammatory activity of ketoprofen was successfully reinstated after decaging of the nontoxic TCOprodrug in live macrophages. Overall, this work expandst he scope of functional groups and the application of decaging reactions to an ew class of drugs.Early research in the fieldo fb ioorthogonal chemistry focused on ligation reactions such as the Staudinger reaction, [1] coppercatalysed azide-alkyne 1,3-dipolar cycloaddition (CuAAC), [2,3] palladium-catalysed cross-couplings, [4] ruthenium-catalysed olefin metatheses, [5] strain-promoted azide-alkyne cycloaddition (SPAAC), [6] tetrazole photoinduced 1,3-dipolar cycloadditions, [7,8] and inverse electron-demandD iels-Alder (iEDDA) tetrazine ligation. [9,10] Of these, the iEDDA reactionb etween transcyclooctene (TCO) and at etrazine is one of the more selective and fastestb ioorthogonal reactions to date. [11] Since it was first introduced by Fox et al., [9] this reactionh as been used in numerous biological applicationss uch as cell and in vivo pretargeting imaging. [12][13][14] Recently,b ioorthogonal cleavage reactions have emerged as promising strategies to control the activation of caged proteins,f luorophores, and small-molecule drugs in living systems. [15] The TCO-tetrazine iEDDA ligation can be re-engineered into ac leavage reaction by placing a leaving group at the allylic positiono fT CO. After the initial cycloaddition and elimination of nitrogen, the 4,5-dihydropyridazine now contains an appropriatelyp laced substituent that eliminates upon tautomerisation. [10] Robillard'sg roup reported the first use of the TCO-tetrazine reaction for bioorthogonal decaging to release amine-containing drugs ( Figure 1A), in which they demonstrated the release of doxorubicin (Dox) from aT CO carbamate prodrug in vitro. [16] They then applied this "click-to-release" strategy to successfullytrigger the release of Dox and monomethyl auristatin E( MMAE) from an antibody-drug conjugate (ADC). [17,18] Mejia Oneto and co-workers also reported targeted in vivo activation of aD ox-TCO carbamate prodrug by injecting an alginate hydrogel modified with tetrazines near the tumour site. [19] Al imitation of the click-toreleases trategy is the need for delivery,a nd therefore optimisation of the pharmacokinetic properties, of both the prodrug and the tetrazine. [20,21] However,t he previously mentioned approaches demonstrate the potential of bioorthogonal decaging reactions for targeted drug activation in vivo.Bioorthogonal chemist...

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Enzymatic synthesis of new C-6-acylated derivatives of NAG-thiazoline and evaluation of their inhibitor activities towards fungal β-N-acetylhexosaminidase

Cited by 13 publications

References 35 publications

Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives

Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives

Dicarboxylic esters: Useful tools for the biocatalyzed synthesis of hybrid compounds and polymers

Tetrazine‐Triggered Release of Carboxylic‐Acid‐Containing Molecules for Activation of an Anti‐inflammatory Drug

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