(+)-(1S,2S,3S,4R,5R)-1-Ammonio-5-hydroxymethylcyclohexane-2,3,4-triol chloride

Chang, Hongjie; Zhu, Jieping; Feng, Xun; Xu, Huaidong

doi:10.1107/s1600536804020902

Cited by 4 publications

(4 citation statements)

References 5 publications

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“…% Pd/C afforded a single isomer 7 in a quantitative yield. We compared the 1 H NMR chemical shift values of the obtained compound with reported validamine ( 2a ) 56 and epi -validamine ( 2b ) 57 to determine the stereochemistry at C(5), Table 4 . Although the proton chemical shift value of 7 at C(5) is similar to 2b , no sound conclusion can be derived due to difference in the chemical environment.…”

Section: Resultsmentioning

confidence: 99%

Stereoselective synthesis of a 4-⍺-glucoside of valienamine and its X-ray structure in complex with Streptomyces coelicolor GlgE1-V279S

Jayasinghe

Thanvi

et al. 2021

Sci Rep

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Glycoside hydrolases (GH) are a large family of hydrolytic enzymes found in all domains of life. As such, they control a plethora of normal and pathogenic biological functions. Thus, understanding selective inhibition of GH enzymes at the atomic level can lead to the identification of new classes of therapeutics. In these studies, we identified a 4-⍺-glucoside of valienamine (8) as an inhibitor of Streptomyces coelicolor (Sco) GlgE1-V279S which belongs to the GH13 Carbohydrate Active EnZyme family. The results obtained from the dose–response experiments show that 8 at a concentration of 1000 µM reduced the enzyme activity of Sco GlgE1-V279S by 65%. The synthetic route to 8 and a closely related 4-⍺-glucoside of validamine (7) was achieved starting from readily available D-maltose. A key step in the synthesis was a chelation-controlled addition of vinylmagnesium bromide to a maltose-derived enone intermediate. X-ray structures of both 7 and 8 in complex with Sco GlgE1-V279S were solved to resolutions of 1.75 and 1.83 Å, respectively. Structural analysis revealed the valienamine derivative 8 binds the enzyme in an E2 conformation for the cyclohexene fragment. Also, the cyclohexene fragment shows a new hydrogen-bonding contact from the pseudo-diaxial C(3)–OH to the catalytic nucleophile Asp 394 at the enzyme active site. Asp 394, in fact, forms a bidentate interaction with both the C(3)–OH and C(7)-OH of the inhibitor. In contrast, compound 7 disrupts the catalytic sidechain interaction network of Sco GlgE1-V279S via steric interactions resulting in a conformation change in Asp 394. These findings will have implications for the design other aminocarbasugar-based GH13-inhibitors and will be useful for identifying more potent and selective inhibitors.

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Section: Resultsmentioning

confidence: 99%

Stereoselective synthesis of a 4-⍺-glucoside of valienamine and its X-ray structure in complex with Streptomyces coelicolor GlgE1-V279S

Jayasinghe

Thanvi

et al. 2021

Sci Rep

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“…47 However, hydrogenation of 30 using 20% Pd(OH) 2 /C afforded a single isomer 7 in a quantitative yield. We compared the 1 H NMR chemical shift values of the obtained compound with reported validamine (2a) 48 and epi-validamine (2b) 49 to determine the stereochemistry at C(5), Table 4. Although the proton chemical shift value of 7 at C( 5) is similar to 2b, no sound conclusion can be derived due to difference in the chemical environment.…”

Section: Kozikowski Et Al Reported That Hydrogenation Of Substitutedmentioning

confidence: 99%

Stereoselective Synthesis of a 4-⍺-Glucoside of Valienamine, Inhibition, and X-Ray Structural Studies Involving a Bacterial Glycoside Hydrolase-Like Enzyme of The GH13 Family

Jayasinghe

Thanvi

et al. 2021

Preprint

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Glycoside hydrolases (GH) are a large family of hydrolytic enzymes found in all domains of life. As such, they control a plethora of normal and pathogenic biological functions. Thus, understanding selective inhibition of GH enzymes at the atomic level can lead to the identification of new classes of therapeutics. In these studies, we identified a 4-⍺-glucoside of valienamine (8) as an inhibitor (IC50 of 484 ± 51 µM) of Streptomyces coelicolor (Sco) GlgE1-V279S which belongs to the GH13 Carbohydrate Active EnZyme (CAZy) family. The synthetic route to 8 and a closely related 4-⍺-glucoside of validamine (7) was achieved starting from readily available D-maltose. A key step in the synthesis was a chelation-controlled addition of vinylmagnesium bromide to a maltose-derived enone intermediate. X-ray structures of both 7 and 8 in complex with Sco GlgE1-V279S were solved to resolutions of 1.75 and 1.78 Å, respectively. Structural analysis revealed the valienamine derivative 8 binds the enzyme in an E2 conformation for the cyclohexene fragment. Also, the cyclohexene fragment shows a new hydrogen-bonding contact from the pseudo-diaxial C(3)-OH to the catalytic nucleophile Asp 394 at the enzyme active site. Asp 394, in fact, forms a bidentate interaction with both the C(3)-OH and C(7)-OH of the inhibitor. In contrast, compound 7 disrupts the catalytic sidechain interaction network of Sco GlgE1-V279S via steric interactions resulting in a conformation change in Asp 394. These findings will have implications for the design other aminocarbasugar-based GH13-inhibitors and will be useful for identifying more potent and selective inhibitors.

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“…H atoms of OH groups were constrained to an ideal geometry, with O-H distances of 0.82 Å and U iso (H) = 1.5U eq (O), but each group was allowed to rotate. In the absence of any significant anomalous scattering, Friedel equivalents were merged prior to the final refinement and the absolute configuration was assigned by reference to the known chirality of (III) established in our previous paper (Chang et al, 2004).…”

Section: C1-n1mentioning

confidence: 99%

(+)-(1S,2S,3S,4R,5R)-N-(1,3-Dihydroxyprop-2-yl)-2,3,4-trihydroxy-5-(hydroxymethyl)-1-cyclohexanaminium picrate

Zhu¹,

Chang²,

Feng

2005

Acta Cryst E

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(+)-(1S,2S,3S,4R,5R)-1-Ammonio-5-hydroxymethylcyclohexane-2,3,4-triol chloride

Abstract: Key indicatorsSingle-crystal X-ray study T = 293 K Mean '(C±C) = 0.005 A Ê Disorder in main residue R factor = 0.047 wR factor = 0.124 Data-to-parameter ratio = 15.9For details of how these key indicators were automatically derived from the article, see

Cited by 4 publications

References 5 publications

Stereoselective synthesis of a 4-⍺-glucoside of valienamine and its X-ray structure in complex with Streptomyces coelicolor GlgE1-V279S

Stereoselective synthesis of a 4-⍺-glucoside of valienamine and its X-ray structure in complex with Streptomyces coelicolor GlgE1-V279S

Stereoselective Synthesis of a 4-⍺-Glucoside of Valienamine, Inhibition, and X-Ray Structural Studies Involving a Bacterial Glycoside Hydrolase-Like Enzyme of The GH13 Family

(+)-(1S,2S,3S,4R,5R)-N-(1,3-Dihydroxyprop-2-yl)-2,3,4-trihydroxy-5-(hydroxymethyl)-1-cyclohexanaminium picrate

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