Synthesis of the enantiomers of XYLNAc and LYXNAc: comparison of β-N-acetylhexosaminidase inhibition by the 8 stereoisomers of 2-N-acetylamino-1,2,4-trideoxy-1,4-iminopentitols

Crabtree, Elizabeth V.; Martínez, R. Fernando; Nakagawa, Shigeaki; Adachi, Isao; Butters, Terry D.; Kato, Atsushi; Fleet, George W. J.; Glawar, Andreas F. G.

doi:10.1039/c4ob00097h

Cited by 20 publications

(13 citation statements)

References 61 publications

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“…A number of small molecule inhibitors against β- N -acetylhexosaminidases have been reported. These include PUGNAc 15 ( 1 ), Nagstatin 16 ( 2 ), NAG-thiazoline 17 ( 3 ), pyrimethamine 18 ( 4 ), iminocyclitols 19 , 20 , and naphthalimides 21–24 . Among these, PUGNAc, Nagstatin, and NAG-thiazoline are the three classic potent inhibitors, which however show non-selectivity between GH20 and GH84 β- N -acetylhexosaminidases 4 , 25 .…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

Shen

Chen

Dong

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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GH20 human β-N-acetylhexosaminidases (hsHex) and GH84 human O-GlcNAcase (hOGA) are involved in numerous pathological processes and emerged as promising targets for drug discovery. Based on the catalytic mechanism and structure of the catalytic domains of these β-N-acetylhexosaminidases, a series of novel naphthalimide moiety-bearing thioglycosides with different flexible linkers were designed, and their inhibitory potency against hsHexB and hOGA was evaluated. The strongest potency was found for compound 15j (Ki = 0.91 µM against hsHexB; Ki > 100 µM against hOGA) and compound 15b (Ki = 3.76 µM against hOGA; Ki = 30.42 µM against hsHexB), which also exhibited significant selectivity between these two enzymes. Besides, inhibitors 15j and 15b exhibited an inverse binding patterns in docking studies. The determined structure–activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific β-N-acetylhexosaminidase inhibitors.

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Section: Introductionmentioning

confidence: 99%

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

Shen

Chen

Dong

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Some are very potent with K i values in the μM to nM range, most of which exhibit almost no selectivity toward function-specific β-GlcNAcases. Representative examples include nagstatin18, PUGNAc19, NAG-thiazoline20, GlcNAcstatinA/B21, pochonicine2223, DNJNAc2425 and other iminocyclitols26272829. The carbohydrate-based TMG-chitotriomycin is the first reported highly-selective inhibitor against chitinolytic β-GlcNAcases from bacteria, fungi and insects, but it is not active toward glycoconjugate-lytic β-GlcNAcases from plant and human3031.…”

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confidence: 99%

A crystal structure-guided rational design switching non-carbohydrate inhibitors' specificity between two β-GlcNAcase homologs

Liu

Guo

Zhou

et al. 2014

Sci Rep

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Selective inhibition of function-specific β-GlcNAcase has great potential in terms of drug design and biological research. The symmetrical bis-naphthalimide M-31850 was previously obtained by screening for specificity against human glycoconjugate-lytic β-GlcNAcase. Using protein-ligand co-crystallization and molecular docking, we designed an unsymmetrical dyad of naphthalimide and thiadiazole, Q2, that changes naphthalimide specificity from against a human glycoconjugate-lytic β-GlcNAcase to against insect and bacterial chitinolytic β-GlcNAcases. The crystallographic and in silico studies reveal that the naphthalimide ring can be utilized to bind different parts of these enzyme homologs, providing a new starting point to design specific inhibitors. Moreover, Q2-induced closure of the substrate binding pocket is the structural basis for its 13-fold increment in inhibitory potency. Q2 is the first non-carbohydrate inhibitor against chitinolytic β-GlcNAcases. This study provides a useful example of structure-based rationally designed inhibitors as potential pharmaceuticals or pesticides.

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“…Here we demonstrate that the reductive amination of a wide range of ketochlorohydrins 9 provides a rapid route to pyrrolidine iminosugars 8 11 25 26 27 28 29 30 31 32 , such as those depicted in Fig. 1 .…”

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confidence: 71%

Direct synthesis of imino-C-nucleoside analogues and other biologically active iminosugars

2015

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Iminosugars have attracted increasing attention as chemical probes, chaperones and leads for drug discovery. Despite several clinical successes, their de novo synthesis remains a significant challenge that also limits their integration with modern high-throughput screening technologies. Herein, we describe a unique synthetic strategy that converts a wide range of acetaldehyde derivatives into iminosugars and imino-C-nucleoside analogues in two or three straightforward transformations. We also show that this strategy can be readily applied to the rapid production of indolizidine and pyrrolizidine iminosugars. The high levels of enantio- and diastereoselectivity, excellent overall yields, convenience and broad substrate scope make this an appealing process for diversity-oriented synthesis, and should enable drug discovery efforts.

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Synthesis of the enantiomers of XYLNAc and LYXNAc: comparison of β-N-acetylhexosaminidase inhibition by the 8 stereoisomers of 2-N-acetylamino-1,2,4-trideoxy-1,4-iminopentitols

Cited by 20 publications

References 61 publications

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

A crystal structure-guided rational design switching non-carbohydrate inhibitors' specificity between two β-GlcNAcase homologs

Direct synthesis of imino-C-nucleoside analogues and other biologically active iminosugars

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