Synthesis of [(2S,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-5-methylfuran-4-carboxylic Acid Derivatives: New Leads as Selective β-Galactosidase Inhibitors

The methanol extract of Sophora flavescens showed a potent glycosidase inhibitory activity. Active components were identified as well-known flavonoid antioxidants: kushenol A (1), (؊)-kurarinone (2), sophoraflavanone G (3), 2-methoxykurarinone (4), kurarinol (5), 8-prenylkaempferol (6), isoxanthohumol (7), kuraridin (8) and maackian (9). All flavonoids were effective inhibitors of a a -glucosidase and b b -amylase. Interestingly, lavandulylated flavanones 1-5 had strong a a -glucosidase inhibitory activities, with IC 50 values of 45 m mM, 68 m mM, 37 m mM, 155 m mM and 179 m mM, respectively. Kushenol A (1) which does not bear a 4-hydroxy group showed selective a a -glucosidase inhibitory activity. Lavandulylated chalcone, kuraridine (8), exhibited IC 50 value of 57 m mM against b b -glucosidase, which is the first report of a chalcone displaying glycosidase inhibition. Results showed that 8-lavandulyl group in B-ring was a key factor of the glycosidase inhibitory activities. The inhibition pattern was noncompetitive for a a -glucosidase, whereas mixed inhibition was observed for b b -amylase.

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“…21) Briefly, 1% starch solution in phosphate buffer was used as a substrate. The starch solution was preincubated for 10 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Both of these are of low abundance in natural sources, [20][21][22][23] and can be obtained in many steps from carbohydrate or noncarbohydrate precursor. Recently, we discovered that some flavonoids isolated from Sophora flavescens showed potent glycosidase inhibitory activities.…”

mentioning

confidence: 99%

Glycosidase Inhibitory Flavonoids from Sophora flavescens

Kim

Ryu

Kang

et al. 2006

Biological & Pharmaceutical Bulletin

102

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“…The inhibitory activity of 64 towardsgalactosidase and -mannosidase is quite similar to that of A powerful inhibitior 85 against -fucosidase is similar to that of compound 63 [77,104]. Compounds with (2R,3R,4S)-configuration (86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97) showed moderate inhibitory activities against -mannosidase [89], and those with a (2R,3S,4R)-configuration (98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109) tend to inhibitglucosidase and -galactosidase [88,89,93,109,110]. The specificity of these compounds was explained based on the similarity with substrate structures of individual enzymes where it was considered that a flexible pyrrolidine structure could adopt a 4 E conformation and 2-and 3-OH groups might mimic the hydroxyl groups of glucopyranosyl cation species (Fig.…”

Section: Cis-diol (B-type) [64777899102-108]mentioning

confidence: 68%

3,4-Dihydroxypyrrolidine as Glycosidase Inhibitor

Suzuki

Nakahara²,

Kanie³

2009

CTMC

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Glycosidases are involved in various important biological processes including digestion of starch in the intestine, oligosaccharide processing inside rough ER and Golgi apparatus, and degradation of glycoconjugates in lysosomes. It is apparent that inhibitors of this class of enzymes are useful in the investigation of biological functions of glycoconjugates. Furthermore, it is believed that these compounds are important as pharmaceuticals. The structures of glycosidase inhibitors can be categorized into two major classes; ground-state mimetics and transition-state mimetics. The former has a chair-shaped six-membered structure that mimics monosaccharides where ring oxygens are often replaced with other elements for an improved binding affinity. On the other hand, the latter possesses a somewhat distorted shape compared with the chair conformation of carbohydrates. One of the ways to derive such distortion is by the introduction of sp2 character into the six-membered ring, and another is by ring contraction to form a five-membered system for the transition-state mimetics. The functions of these transition-state mimetics are often unpredictable regarding inhibitory activity and enzyme specificity. This review focuses on such "difficult to predict" species in an attempt to extract information or common aspects for the future development of inhibitors of glycosidases based on transition-state mimetics.

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“…We have also found [6] that stereoisomeric derivatives of type 4 are specific inhibitors of various b-galactosidases. We describe here the details of the synthesis of these inhibitors that can be viewed as a new type of dideoxy-iminosugar-derived C-nucleoside analogue.…”

mentioning

confidence: 66%

Synthesis and Glycosidase Inhibitory Activities of 5‐(1′,4′‐Dideoxy‐1′,4′‐imino‐D‐erythrosyl)‐2‐methyl‐3‐furoic Acid (=5‐[(3S,4R)‐3,4‐Dihydroxypyrrolidin‐2‐yl]‐2‐methylfuran‐3‐carboxylic Acid) Derivatives: New Leads as Selective α‐L‐Fucosidase and β‐Galactosidase Inhibitors

Vargas

Robina

Demange

et al. 2003

Helvetica Chimica Acta

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The GarcÌa-Gonza¬lez reaction of d-glucose and ethyl acetoacetate generated ethyl 5-[(1'S)-d-erythrosyl]-2-methyl-3-furoate (5), which was converted to ethyl 5-[(1'R)-1',4'-dideoxy-1',4'-imino-d-erythrosyl]-2-methyl-3-furoate (3c) and to ethyl 5-[(1'S)-1',4'-dideoxy-1',4'-imino-d-erythrosyl]-2-methyl-3-furoate (4c). Similar methods were developed to generate other carboxylic acid derivatives such as methyl (see 3e and 4e), isopropyl (see 3f), and butyl esters (see 3g), S-phenyl (see 3a) and S-ethyl thioesters (see 3m), N-benzylcarboxamides 3b and 4b, glycine-derived amide 3h, and N-phenyl (see 3i), N-isopropyl (see 3j and 4j), N,N-diethyl-(see 3k and 4k), and N-ethyl-carboxamides (see 3l). All the new 5-(1',4'-dideoxy-1',4'-imino-d-erythrosyl)-3-furoic acid ( 5-[(3S,4R)-3,4-dihydroxypyrrolidin-2-yl)furan-3-carboxylic acid) derivatives 3 and 4 were assayed for inhibitory activity towards 25 commercially available glycosidases. Derivative 3a with a S-phenyl thioester group is a good and selective a-l-fucosidase inhibitor (K i 2 ± 4 mm), whereas 4b (with a N-benzylcarboxamide group) is a good b-galactosidase inhibitor.Introduction. ± Derivatives of pyrrolidine-3,4-diols ( 1,4-dideoxy-1,4-iminoalditols) constitute an important class of glycosidase inhibitors [1] although, in some cases, there is a lack of selectivity due to the higher conformational flexibility compared to 1,5-dideoxy-1,5-iminoalditols and other imino-bicyclic structures. For instance, simple meso-pyrrolidine-3,4-diol (1) is a weak and nonselective inhibitor [2] that presents activity towards several glycosidases.

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Synthesis of [(2S,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-5-methylfuran-4-carboxylic Acid Derivatives: New Leads as Selective β-Galactosidase Inhibitors

Cited by 29 publications

References 43 publications

Glycosidase Inhibitory Flavonoids from Sophora flavescens

Glycosidase Inhibitory Flavonoids from Sophora flavescens

3,4-Dihydroxypyrrolidine as Glycosidase Inhibitor

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