The UDP-Galp mutase catalyzed isomerization: synthesis and evaluation of 1,4-anhydro-β-d-galactopyranose and its [2.2.2] methylene homologue

Sadeghi-Khomami, Ali; Forcada, Tatiana J.; Wilson, Claire; Sanders, D.A.R.; Thomas, Neil R.

doi:10.1039/b917409e

Cited by 15 publications

(9 citation statements)

References 74 publications

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“…13 NMR data were in accordance with previously reported values. 41 Methyl 2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranoside (49). NaH (60%, 3.00 g 75.0 mmol, 3.9 eq.)…”

Section: Organic Synthesismentioning

confidence: 99%

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Stable analogues of nojirimycin – synthesis and biological evaluation of nojiristegine and manno-nojiristegine

et al. 2015

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Two novel iminosugars called nojiristegines, being structural hybrids between nor-tropane alkaloid calystegine and nojirimycins, have been synthesised and found to be stable molecules despite the presence of a hemiaminal functionality. The synthesised iminosugars were evaluated against a panel of glycosidases and the best inhibition (IC50), found against α-glucosidases, was in the micromolar region. The compounds were also evaluated as potential antibiotics but no useful level of activity was observed.

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“…13 NMR data were in accordance with previously reported values. 41 Methyl 2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranoside (49). NaH (60%, 3.00 g 75.0 mmol, 3.9 eq.)…”

Section: Organic Synthesismentioning

confidence: 99%

“…NMR data was in accordance with previously reported values. 41 Methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (50). BH 3 •THF complex (1 M solution in THF, 80 mL, 80 mmol, 4.9 eq.)…”

Section: Organic Synthesismentioning

confidence: 99%

Stable analogues of nojirimycin – synthesis and biological evaluation of nojiristegine and manno-nojiristegine

et al. 2015

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“…14,16 A number of groups have developed inhibitors against UGM, with varying degrees of success. [17][18][19][20][21][22][23][24] These potential inhibitors have included mechanism-based inhibitors 19,23,25-29 heterocyclic molecules obtained from high throughput screening of chemical libraries 18,30 and substrate analogue inhibitors. 17,20,31 UGM inhibitors have been identified that block the growth of mycobacterial cells 18 and a pyrazole-based compound was demonstrated to possess both UGM inhibitory properties and broad anti-mycobacterial activities.…”

Section: Introductionmentioning

confidence: 99%

Structural Basis of Ligand Binding to UDP-Galactopyranose Mutase from Mycobacterium tuberculosis Using Substrate and Tetrafluorinated Substrate Analogues

et al. 2015

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UDP-Galactopyranose mutase (UGM) is a flavin-containing enzyme that catalyses the reversible conversion of UDP-Galactopyranose (UDP-Galp) to UDP-Galactofuranose (UDPGalf) and plays a key role in the biosynthesis of the mycobacterial cell wall galactofuran. A soluble, active form of UGM from Mycobacterium tuberculosis (MtUGM) was obtained from a dual His 6 -MBP tagged MtUGM construct. We present the first complex structures of MtUGM with bound substrate UDP-Galp (both oxidized flavin and reduced flavin). In addition, we have determined the complex structures of MtUGM with inhibitors (UDP and the dideoxytetrafluorinated analogs of both UDP-Galp (UDP-F 4 -Galp) and UDP-Galf (UDP-F 4 -Galf)), which represent the first complex structures of UGM with an analogue in the furanose form, as well as the first structures of dideoxy-tetrafluorinated sugar analogs bound to a protein. These structures provide detailed insight into ligand recognition by MtUGM and show a similar overall binding mode as reported for other prokaryotic UGMs. The binding of the ligand induces conformational changes in the enzyme, allowing ligand binding and active site closure. In addition, the complex structure of MtUGM with UDP-F 4 -Galf reveals the first detailed insight into how the furanose moiety binds to UGM. In particular, this study confirmed that the furanoside adopts a high energy conformation ( 4 E) within the catalytic pocket. Moreover, these investigations provide structural insights to the enhanced binding of the dideoxy-tetrafluorinated sugars compared to unmodified analogs. These results will help in the design of carbohydrate mimetics and drug development, and show the enormous possibilities on the use of polyfluorination in the design of carbohydrate mimetics.

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“…Because some compounds selected through this procedure were no longer commercially available they were replaced by others with slightly lower scores and/or greater structural diversity. Figure 2 shows the chemical structures of LeadQuest compounds selected based on their high scores together with a number of compounds designed to mimic putative intermediates in the reaction pathway 7c,f,22…”

Section: Resultsmentioning

confidence: 99%

Identification of Novel Inhibitors of UDP‐Galactopyranose Mutase by Structure‐Based Virtual Screening

Partha

Sadeghi-Khomami

Cren

et al. 2011

Molecular Informatics

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UDP-galactopyranose mutase (UGM) is a flavo-enzyme involved in the bacterial cell wall biosynthesis. UGM catalyzes the reversible isomerization of UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf). UDP-Galf is the activated precursor of galactofuranose (Galf) residues that are essential components of the cell wall of certain pathogenic bacteria such as Klebsiella pneumoniae and Mycobacterium tuberculosis. Neither UGM nor Galf residues are found in humans, making Galf biosynthesis a potential drug target for developing antibacterial agents. We report the identification of novel inhibitors of UGM by in silico docking of the LeadQuest compound database against UGM from Escherichia coli. The 13 most promising inhibitors were then evaluated against K. pneumonia and M. tuberculosis UGMs by enzyme inhibition studies. Two inhibitors were identified with IC50 values of ∼1 µM and subsequently these compounds were docked into the recently solved X-ray structure of Deinococcus radiodurans UGM. The structure-activity relationships of the initial 13 compounds evaluated as inhibitors are discussed.

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The UDP-Galp mutase catalyzed isomerization: synthesis and evaluation of 1,4-anhydro-β-d-galactopyranose and its [2.2.2] methylene homologue

Cited by 15 publications

References 74 publications

Stable analogues of nojirimycin – synthesis and biological evaluation of nojiristegine and manno-nojiristegine

Stable analogues of nojirimycin – synthesis and biological evaluation of nojiristegine and manno-nojiristegine

Structural Basis of Ligand Binding to UDP-Galactopyranose Mutase from Mycobacterium tuberculosis Using Substrate and Tetrafluorinated Substrate Analogues

Identification of Novel Inhibitors of UDP‐Galactopyranose Mutase by Structure‐Based Virtual Screening

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