A new access to polyhydroxy piperidines of the azasugar class: synthesis and glycosidase inhibition studies

Pandey, Ganesh; Kapur, Manmohan; Khan, M. Islam; Gaikwad, Sushama M.

doi:10.1039/b307455b

Cited by 54 publications

(26 citation statements)

References 33 publications

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“…Considering the unsatisfactory route to 9 from D-galactose (16 steps, 3% overall yield), we decided to synthesise the diastereoisomeric glycarolactams 8 -11 from the aldehyde 35 (Scheme 3). This aldehyde may be derived from tartaric acid, and although (R,R)-and (S,S)-tartaric acid (L-and D-threaric acid) and their derivatives are among the most extensively used starting materials of the chiral pool [37], there are only a few examples of syntheses of (chain-extended) carbohydrates and analogues from tartrates, such as the syntheses of deoxynojirimycin [38], castanospermine [39], polyhydroxy piperidines [40], conduritol [41], and a myo-inositol derivative [42].…”

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confidence: 99%

Synthesis of Glycaro‐1,5‐lactams and Tetrahydrotetrazolopyridine‐5‐carboxylates: Inhibitors of β‐D‐Glucuronidase and α‐L‐Iduronidase

Pabba

Rempel

Withers

et al. 2006

Helvetica Chimica Acta

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The known glucaro-1,5-lactam 8, its diastereoisomers 9 -11, and the tetrahydrotetrazolopyridine-5-carboxylates 12 -14 were synthesised as potential inhibitors of b-D-glucuronidases and a-L-iduronidases. The known 2,3-di-O-benzyl-4,6-O-benzylidene-D-galactose (16) was transformed into the D-galactaroand L-altraro-1,5-lactams 9 and 11 via the galactono-1,5-lactam 21 in twelve steps and in an overall yield of 13 and 2%, respectively. A divergent strategy, starting from the known tartaric anhydride 41, led to the D-glucaro-1,5-lactam 8, D-galactaro-1,5-lactam 9, L-idaro-1,5-lactam 10, and L-altraro-1,5-lactam 11 in ten steps and in an overall yield of 4 -20%. The anhydride 41 was transformed into the L-thre-A C H T U N G T R E N N U N G uronate 46. Olefination of 46 to the (E)-or (Z)-alkene 47 or 48 followed by reagent-or substrate-controlled dihydroxylation, lactonisation, azidation, reduction, and deprotection led to the lactams 8 -11. The tetrazoles 12 -14 were prepared in an overall yield of 61 -81% from the lactams 54, 28, and 67, respectively, by treatment with Tf 2 A C H T U N G T R E N N U N G O and NaN 3 , followed by saponification, esterification, and hydrogen-A C H T U N G T R E N N U N G olysis. The lactams 8 -11 and 40 and the tetrazoles 12 -14 are medium-to-strong inhibitors of b-D-glucuronidase from bovine liver. Only the L-ido-configured lactam 10 (K i = 94 mM) and the tetrazole 14Introduction. -b-D-Glucuronidases (EC 3.2.1.31, family 2) 1 ) and a-L-iduronidases (EC 3.2.1.76, family 39) remove glycuronic acid residues from the non-reducing end of glycosaminoglycans such as chondroitin sulfate and hyaluronic acid.

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confidence: 99%

Synthesis of Glycaro‐1,5‐lactams and Tetrahydrotetrazolopyridine‐5‐carboxylates: Inhibitors of β‐D‐Glucuronidase and α‐L‐Iduronidase

Pabba

Rempel

Withers

et al. 2006

Helvetica Chimica Acta

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“…DNJ also inhibits and -glycosidases. Changing the position of the heterocycle nitrogen atom to the anomeric carbon position of DNJ pyranosidic ring in so-called 1-azasugars increases the inhibition of -glucosidases 440 times without affecting -glycosidases (112). Isofagomine (IFG) (compound 8; Fig.…”

Section: Therapeutic Noncovalent Inhibitorsmentioning

confidence: 99%

Distinguishing the differences in β-glycosylceramidase folds, dynamics, and actions informs therapeutic uses

Bdira

Artola

Overkleeft

et al. 2018

Journal of Lipid Research

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Glycoconjugates play essential roles in diverse biological processes and abnormalities and have been linked to multiple pathologies. The staggering structural diversity of glycoconjugates stems from the almost infinite possible combinations by which multiple monosaccharide building blocks may be linked with each other (1). For instance, 1,056 unique trisaccharides can be formed just from 3 different monosaccharides. Polysaccharides are very stable compounds: their spontaneous hydrolysis takes place at a rate of 10 15 s 1 , corresponding to a half-life of 4.7 million years (2). To allow for the efficient metabolism of glycoconjugates, enzymes have evolved as specialized catalysts. In most organisms, an estimated 1% to 3% of the genes encode carbohydrate-active enzymes (3). Among these are glycoside hydrolases (GHs) that can enhance the rate of hydrolysis of specific carbohydrate glycosidic bonds in glycoconjugates more than 10 17 times (2). These GH enzymes show marked specificity regarding number, position, and configuration of the hydroxyl groups in their substrate sugar. They are widely applied in biotechnology, for example, in biofuel production, paper pulp bleaching, and the food industry (4, 5). Likewise, specific GH inhibitors are extensively used as agrochemicals and therapeutic agents (6-8). Abnormalities in GHs underlie metabolic disorders in humans, for instance, inherited lysosomal storage disorders and lactose intolerance (9, 10). GH enzymes differ in substrate specificity, mode of enzymatic attack Abstract Glycosyl hydrolases (GHs) are carbohydrate-active enzymes that hydrolyze a specific -glycosidic bond in glycoconjugate substrates; -glucosidases degrade glucosylceramide, a ubiquitous glycosphingolipid. GHs are grouped into structurally similar families that themselves can be grouped into clans. GH1, GH5, and GH30 glycosidases belong to clan A hydrolases with a catalytic (/) 8 TIM barrel domain, whereas GH116 belongs to clan O with a catalytic (/) 6 domain. In humans, GH abnormalities underlie metabolic diseases. The lysosomal enzyme glucocerebrosidase (family GH30), deficient in Gaucher disease and implicated in Parkinson disease etiology, and the cytosol-facing membrane-bound glucosylceramidase (family GH116) remove the terminal glucose from the ceramide lipid moiety. Here, we compare enzyme differences in fold, action, dynamics, and catalytic domain stabilization by binding site occupancy. We also explore other glycosidases with reported glycosylceramidase activity, including human cytosolic -glucosidase, intestinal lactase-phlorizin hydrolase, and lysosomal galactosylceramidase. Last, we describe the successful translation of research to practice: recombinant glycosidases and glucosylceramide metabolism modulators are approved drug products (enzyme replacement therapies). Activity-based probes now facilitate the diagnosis of enzyme deficiency and screening for compounds that interact with the catalytic pocket of glycosidases. Future research may deepen the understanding of the function...

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“…Therefore, the development of new strategies that allow the stereoselective synthesis of hydroxylated piperidines starting from non-carbohydrate precursors constitutes an area of current interest. [4][5][6][7] Recently, hydroxylated 2-arylpiperidines have been shown to act as inhibitors of rhamnosyl-processing enzymes and to be potentially useful against tuberculosis. [8] In general, functionalized piperidines and the synthetic methodologies used for their preparation are of considerable interest.…”

Section: Introductionmentioning

confidence: 99%

1‐Alkoxyamino‐2‐nitroalkanes as Key Building Blocks for a Chemo‐ and Diastereoselective Synthesis of a New Type of Polyfunctionalized N‐Alkoxypiperidine

et al. 2010

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A highly efficient conversion of β-nitrostyrenes into a new kind of functionalized N-alkoxy-2-hydroxypiperidine in two steps was developed, giving excellent yields and diastereoselectivity. The prepared compounds are the first examples of N-alkoxy-2-hydroxypiperidines. The synthetic approach involved the conjugate addition of alkoxyamines to β-nitrostyrenes, followed by Michael addition of the isolated nitro-

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A new access to polyhydroxy piperidines of the azasugar class: synthesis and glycosidase inhibition studies

Cited by 54 publications

References 33 publications

Synthesis of Glycaro‐1,5‐lactams and Tetrahydrotetrazolopyridine‐5‐carboxylates: Inhibitors of β‐D‐Glucuronidase and α‐L‐Iduronidase

Synthesis of Glycaro‐1,5‐lactams and Tetrahydrotetrazolopyridine‐5‐carboxylates: Inhibitors of β‐D‐Glucuronidase and α‐L‐Iduronidase

Distinguishing the differences in β-glycosylceramidase folds, dynamics, and actions informs therapeutic uses

1‐Alkoxyamino‐2‐nitroalkanes as Key Building Blocks for a Chemo‐ and Diastereoselective Synthesis of a New Type of Polyfunctionalized N‐Alkoxypiperidine

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