Stereoselective synthesis of (2S,3S,4R,5S)-5-methylpyrrolidine-3,4-diol derivatives that are highly selective α-l-fucosidase inhibitors

Vargas, Ângelo; Carmona, Ana T.; Mora, Federico; Vogel, Pierre; Robina, Inmaculada

doi:10.1039/b508855k

Cited by 36 publications

(14 citation statements)

References 28 publications

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“…[43,44] The activity of compound 6, not previously reported to the best of our knowledge, is amongst the highest reported for pyrrolidine and piperidine type iminosugars. [45][46][47][48][49] Other pyrrolidine derivatives with similar stereochemistry (i.e., 3S,4R,5S) have also been reported as strong inhibitors of al-fucosidase, [50][51][52] while some diastereomerically related isomers of 5 and 6 have shown much lower activities (e.g. K i = 165 mm for the 2R,3R,4R,5R isomer [46] ), suggesting a strong stereochemical demand of the a-l-fucosidase active site.…”

Section: Wwwchemeurjorgmentioning

confidence: 99%

Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

Calveras

Egido‐Gabás

Gómez

et al. 2009

Chemistry A European J

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The chemoenzymatic synthesis of a collection of pyrrolidine-type iminosugars generated by the aldol addition of dihydroxyacetone phosphate (DHAP) to C-alpha-substituted N-Cbz-2-aminoaldehydes derivatives, catalyzed by DHAP aldolases is reported. L-fuculose-1-phosphate aldolase (FucA) and L-rhamnulose-1-phosphate aldolase (RhuA) from E. coli were used as biocatalysts to generate configurational diversity on the iminosugars. Alkyl linear substitutions at C-alpha were well tolerated by FucA catalyst (i.e., 40-70 % conversions to aldol adduct), whereas no product was observed with C-alpha-alkyl branched substitutions, except for dimethyl and benzyl substitutions (20 %). RhuA was the most versatile biocatalyst: C-alpha-alkyl linear groups gave the highest conversions to aldol adducts (60-99 %), while the C-alpha-alkyl branched ones gave moderate to good conversions (50-80 %), with the exception of dimethyl and benzyl substituents (20 %). FucA was the most stereoselective biocatalyst (90-100 % anti (3R,4R) adduct). RhuA was highly stereoselective with (S)-N-Cbz-2-aminoaldehydes (90-100 % syn (i.e., 3R,4S) adduct), whereas those with R configuration gave mixtures of anti/syn adducts. For iPr and iBu substituents, RhuA furnished the anti adduct (i.e., FucA stereochemistry) with high stereoselectivity. Molecular models of aldol products with iPr and iBu substituents and as complexes with the RhuA active site suggest that the anti adducts could be kinetically preferred, while the syn adducts would be the equilibrium products. The polyhydroxylated pyrrolidines generated were tested as inhibitors against seven glycosidases. Among them, good inhibitors of alpha-L-fucosidase (IC50=1-20 microM), moderate of alpha-L-rhamnosidase (IC50=7-150 microM), and weak of alpha-D-mannosidase (IC50=80-400 microM) were identified. The apparent inhibition constant values (Ki) were calculated for the most relevant inhibitors and computational docking studies were performed to understand both their binding capacity and the mode of interaction with the glycosidases.

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Section: Wwwchemeurjorgmentioning

confidence: 99%

Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

Calveras

Egido‐Gabás

Gómez

et al. 2009

Chemistry A European J

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“…[6][7][8][9] We have shown that the presence of an additional aromatic or heteroaromatic binding component close to the five membered iminocyclitol increases notably their inhibitory activity (1 10 vs. 2, 8 Fig. 1).…”

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confidence: 99%

Rapid discovery of potent α-fucosidase inhibitors by in situ screening of a library of (pyrrolidin-2-yl)triazoles

et al. 2014

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The synthesis of a small library of (pyrrolidin-2-yl)triazoles via copper catalysed cycloaddition of an alkynyl iminocyclopentitol and a set of commercial and synthetic azides has been achieved. The in situ screening for the activity towards α-fucosidase of the resulting triazoles has allowed the identification of one of the most potent and selective pyrrolidine derived inhibitors of this enzyme (Ki = 4 nM).

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“…During the synthesis of the pyrrolidine antibiotic (+)-anisomycin, Rao and co-workers used an intramolecular displacement of a mesylate with a Cbz protected amine. [49] Eustache and co-workers also relied on the introduction of a mesylate and subsequent intramolecular displacement by a protected amine during the synthesis of an arabinofuranosyltransferase inhibitor, [50] while, en route to the synthesis of aminopyrrolidinediols, Robina and coworkers [51] introduced a mesylate group then an azide whose subsequent reduction led to intramolecular cyclisation. Similar azide/reduction methodology was used by Clinch et al when preparing the enantiomer of the azanucleoside immucillin H. [52] Here, protected lyxonolactone 82 was reduced to diol 83, di-mesylated to provide 84, then mono-substituted (Ǟ 85).…”

Section: Substitution Reactionsmentioning

confidence: 98%

Recent Developments in the Synthesis of Pyrrolidine‐Containing Iminosugars

et al. 2010

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As noted inhibitors of glycosidases, iminosugars have enormous therapeutic potential in the treatment of a number of diseases such as cancer, diabetes, and lysosomal storage disorders. Accordingly, much effort has been expended over the past decades in developing novel and efficient methodologies for the synthesis of iminosugars. This microreview highlights recent (post 2005) developments in the synthesis of pyrrolidine‐containing iminosugars and includes discussions of methodologies such as ring‐closing metathesis, aldol and pericyclic reactions, and protecting‐group free strategies.

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Stereoselective synthesis of (2S,3S,4R,5S)-5-methylpyrrolidine-3,4-diol derivatives that are highly selective α-l-fucosidase inhibitors

Abstract: N-Phenylaminomethyl benzimidazolyl moieties attached at C-2 of (2S,3S,4R,5S)-5-methylpyrrolidine-3,4-diol increase the potency and selectivity of the inhibitory activity of these systems towards alpha-L-fucosidases.

Cited by 36 publications

References 28 publications

Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

Rapid discovery of potent α-fucosidase inhibitors by in situ screening of a library of (pyrrolidin-2-yl)triazoles

Recent Developments in the Synthesis of Pyrrolidine‐Containing Iminosugars

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