Syntheses of validamine, epi-validamine, and valienamine, three optically active pseudo-amino-sugars, from D-glucose.

Yoshikawa, Masayuki; Cheon, Bae; Okaichi, Yoshihiko; Takinami, Yoshihiko; Yokokawa, Yoshihiro; Kitagawa, Isao

doi:10.1248/cpb.36.4236

Cited by 31 publications

(28 citation statements)

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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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“…protective benzyl groups gives valiolamine (5). Similar synthesis routes to pseudosugars were followed by PAULSEN and DEYN (1987) and by ALTENBACH (1993), whereas Kitagawa, in his syntheses of valiolamine and valienamine, first coupled the C-l synthon nitro methane with the 5-position of o-glucose and then completed the ring c\osure by an additional coupling to position 1 (YOSHIKAWA et al 1988). Valienamine (4), readily available by microbiological degradat ion of validamycin, can be converted in a few steps into the more effective valiolamine (5) by way of the cyc\ic carbamate 24 .…”

Section: Acmentioning

confidence: 79%

Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

Junge¹,

Matzke²,

Stoltefuß³

1996

Oral Antidiabetics

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A. IntroductionWhen intestinal sucrase and pancreatic a-amylase were identified at Bayer as new targets for improved diabetes therapy (PULS et al. 1973), the problem remained of the best way to find a potent and selective inhibitor of these enzymes. The medicinal chemist today has two alternatives in the search for a first lead compound, firstly the screening of thousands of compounds with maximum structural diversity in a random screening approach, or secondly the rational design of a lead compound, when the biochemical mechanism and the structure of the enzyme are weIl known. In the late 1960s, when we started to look for such potent and selective inhibitors, we had to choose the random screening approach, relying mainly on testing of extracts of the culture broths of microorganisms.Today the mechanism of enzymatic splitting of sucrose by intestinal sucrase is fairly weIl understood. First the glucosidic oxygen atom of sucrose is protonated via a carboxyl group of the enzyme. The splitting of the glucosidic C-O bond is further facilitated by the glucosyl cation being stabilized by a second carboxylate group of the enzyme (COGOLI and SEMENZA 1975). FinaIly, the glucosyl cation reacts with water to give the products 0-glucose and o-fructose. The protonated sucrose molecule land the glucosyl cation 11 are two high-energy intermediates of the enzymatic reaction. Today we know that mimics of such high-energy intermediates are often potent inhibitors of the enzyme. Accordingly, compounds similar in structure to o-glucose but with an easily protonated basic N-atom either in the position of the anomeric oxygen atom (inhibitor type I) or in the position of the ring oxygen atom (inhibitor type 11) should be potent inhibitors of sucrase (Fig. 1). Interestingly, both types of inhibitors represented by either acarbose or I-deoxynojirimycin were found in our random screening. In the foIlowing sections these two types of inhibitors are not discussed in a historical order but under structural criteria. Not included in this discussion are the a-amylase inhibitors of protein nature because there is no evidence that they will find any therapeutic application.

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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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Syntheses of validamine, epi-validamine, and valienamine, three optically active pseudo-amino-sugars, from D-glucose.

Cited by 31 publications

References 0 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

Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

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

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