Synthesis and α-Glucosidase II inhibitory activity of valienamine pseudodisaccharides relevant to N-glycan biosynthesis

Cumpstey, Ian; Ramstadius, Clinton; Borbas, K. Eszter; Alonzi, Dominic S.; Butters, Terry D.

doi:10.1016/j.bmcl.2011.07.046

Cited by 8 publications

(4 citation statements)

References 35 publications

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“…6 α-Glucosidase inhibitors, the effective therapeutic agents for type II diabetes and obesity, have a widespread clinical use for managing blood glucose levels. However, most of the developed α-glucosidase inhibitors are sugar mimics requiring multiple steps from carbohydrates and noncarbohydrates, 7 including 1-deoxynojirimycin, 8 valienamine, 9 and acarbose. 10 Consequently, it is necessary to utilize a simple and economical synthetic method to obtain α-glucosidase inhibitors.…”

Section: ■ Introductionmentioning

confidence: 99%

α-Glucosidase Inhibitors via Green Pathway: Biotransformation for Bicoumarins Catalyzed byMomordica charantiaPeroxidase

Wang

2013

J. Agric. Food Chem.

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Peroxidase extracted from Momordica charantia catalyzed the H(2)O(2)-dependent oxidative coupling of 7-hydroxy-4-methylcoumarin to form four new dimers (1-4) and two known ones (5, 6). The structures, including the absolute configurations of axially chiral compounds, were unambiguously characterized by NMR spectroscopy, online HPLC-CD, and a variety of computational methods. Bioactive experiments demonstrated that compounds 1 and 2 had significant inhibitory effects on yeast α-glucosidase, much better than the controls. Noncompetitive binding mode was found by the graphical analysis of steady-state inhibition data. The mechanism of enzymatic inhibition confirmed in some depth that the inhibitors altered the secondary structure of α-glucosidase by decreasing the α-helix and increasing the β-sheet content. In summary, bicoumarins 1 and 2 might be exploited as the lead compounds for further research of antidiabetic agents, and this research provided a "green" method to synthesize compounds with the chiral biaryl axis generally calling for multistep reactions in organic chemistry.

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Section: ■ Introductionmentioning

confidence: 99%

α-Glucosidase Inhibitors via Green Pathway: Biotransformation for Bicoumarins Catalyzed byMomordica charantiaPeroxidase

Wang

2013

J. Agric. Food Chem.

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“…For target 13, intermediate 10 was converted to an intermediate allylic bromide 26 (α:β, 1:1) formed using phosphorous tribromide in 55% yield (Cumpstey et al, 2011). Compound 27 was obtained by subjecting the Frontiers in Chemistry frontiersin.org mixture of allylic bromide 26 to an excess of cyclohexylamine and triethylamine.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of C7/C8-cyclitols and C7N-aminocyclitols from maltose and X-ray crystal structure of Streptomyces coelicolor GlgEI V279S in a complex with an amylostatin GXG–like derivative

Thanvi

Jayasinghe²,

Kapil³

et al. 2022

Front. Chem.

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C7/C8-cyclitols and C7N-aminocyclitols find applications in the pharmaceutical sector as α-glucosidase inhibitors and in the agricultural sector as fungicides and insecticides. In this study, we identified C7/C8-cyclitols and C7N-aminocyclitols as potential inhibitors of Streptomyces coelicolor (Sco) GlgEI-V279S based on the docking scores. The protein and the ligand (targets 11, 12, and 13) were prepared, the states were generated at pH 7.0 ± 2.0, and the ligands were docked into the active sites of the receptor via Glide™. The synthetic route to these targets was similar to our previously reported route used to obtain 4-⍺-glucoside of valienamine (AGV), except the protecting group for target 12 was a p-bromobenzyl (PBB) ether to preserve the alkene upon deprotection. While compounds 11–13 did not inhibit Sco GlgEI-V279S at the concentrations evaluated, an X-ray crystal structure of the Sco GlgE1-V279S/13 complex was solved to a resolution of 2.73 Å. This structure allowed assessment differences and commonality with our previously reported inhibitors and was useful for identifying enzyme–compound interactions that may be important for future inhibitor development. The Asp 394 nucleophile formed a bidentate hydrogen bond interaction with the exocyclic oxygen atoms (C(3)-OH and C(7)-OH) similar to the observed interactions with the Sco GlgEI-V279S in a complex with AGV (PDB:7MGY). In addition, the data suggest replacing the cyclohexyl group with more isosteric and hydrogen bond–donating groups to increase binding interactions in the + 1 binding site.

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“…22,23 While iminosugars based on DNJ have been studied extensively as ER α-glucosidase inhibitors and potential antiviral therapeutics, 12−18 as noted above, valienamines and valiolamines, which contain an exocyclic amine group, have not been studied, with the exception of several valienamine derivatives that showed limited α-GluII inhibitory activity. 24 Accordingly, we synthesized a series of N-substituted valiolamine derivatives, measured their ability to inhibit ER α-GluI and α-GluII, and tested them for activity against dengue virus and SARS-CoV-2 in vitro. We determined high-resolution crystal structures of α-GluII in complex with valiolamine and 10 valiolamine derivatives.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The search for compounds to treat type 2 diabetes by preventing saccharide hydrolysis has led to three clinically approved inhibitors of intestinal (as opposed to ER) α-glucosidases: miglitol, acarbose, and voglibose . These glycomimetics employ different amino sugar scaffolds: the iminosugar 1-deoxynojirimycin (DNJ) for miglitol, valienamine ((1 S ,2 S ,3 R ,6 S )-6-amino-4-(hydroxymethyl)cyclohex-4-ene-1,2,3-triol) for acarbose, and valiolamine ((1 S ,2 S ,3 R ,4 S ,5 S )-5-amino-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetraol) for voglibose. , While iminosugars based on DNJ have been studied extensively as ER α-glucosidase inhibitors and potential antiviral therapeutics, − as noted above, valienamines and valiolamines, which contain an exocyclic amine group, have not been studied, with the exception of several valienamine derivatives that showed limited α-GluII inhibitory activity . Accordingly, we synthesized a series of N-substituted valiolamine derivatives, measured their ability to inhibit ER α-GluI and α-GluII, and tested them for activity against dengue virus and SARS-CoV-2 in vitro .…”

Section: Introductionmentioning

confidence: 99%

N-Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum α-Glucosidases I and II with Antiviral Activity

et al. 2021

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Most enveloped viruses rely on the host cell endoplasmic reticulum (ER) quality control (QC) machinery for proper folding of glycoproteins. The key ER α-glucosidases (α-Glu) I and II of the ERQC machinery are attractive targets for developing broad-spectrum antivirals. Iminosugars based on deoxynojirimycin have been extensively studied as ER α-glucosidase inhibitors; however, other glycomimetic compounds are less established. Accordingly, we synthesized a series of N-substituted derivatives of valiolamine, the iminosugar scaffold of type 2 diabetes drug voglibose. To understand the basis for up to 100,000-fold improved inhibitory potency, we determined high-resolution crystal structures of mouse ER α-GluII in complex with valiolamine and 10 derivatives. The structures revealed extensive interactions with all four α-GluII subsites. We further showed that N-substituted valiolamines were active against dengue virus and SARS-CoV-2 in vitro. This study introduces valiolamine-based inhibitors of the ERQC machinery as candidates for developing potential broad-spectrum therapeutics against the existing and emerging viruses.

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Synthesis and α-Glucosidase II inhibitory activity of valienamine pseudodisaccharides relevant to N-glycan biosynthesis

Cited by 8 publications

References 35 publications

α-Glucosidase Inhibitors via Green Pathway: Biotransformation for Bicoumarins Catalyzed byMomordica charantiaPeroxidase

α-Glucosidase Inhibitors via Green Pathway: Biotransformation for Bicoumarins Catalyzed byMomordica charantiaPeroxidase

Synthesis of C7/C8-cyclitols and C7N-aminocyclitols from maltose and X-ray crystal structure of Streptomyces coelicolor GlgEI V279S in a complex with an amylostatin GXG–like derivative

N-Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum α-Glucosidases I and II with Antiviral Activity

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