New Synthetic Seven‐Membered 1‐Azasugars Displaying Potent Inhibition Towards Glycosidases and Glucosylceramide Transferase

Li, Hongqing; Liu, Tao; Zhang, Yongmin; Favre, Sylvain; Bello, Claudia; Vogel, Pierre; Butters, Terry D.; Oikonomakos, Nikos G.; Marrot, Jérôme; Blériot, Yves

doi:10.1002/cbic.200700496

Cited by 52 publications

(33 citation statements)

References 60 publications

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“…Water was Milli-Q™ grade. Non-alkylated parent compounds of inhibitors 1-4, were N-butylated and purified as described [5]. The structures are shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…These were found to be potent ß-glucosidase inhibitors with weak activity towards α-glucosidases and α-mannosidases using in vitro assays [5].…”

Section: Introductionmentioning

confidence: 99%

“…A new series of compounds based upon an N-alkylated polyhydroxylated azepane scaffold have been synthesised with D-glucose and L-idose-like configuration [5]. These were found to be potent ß-glucosidase inhibitors with weak activity towards α-glucosidases and α-mannosidases using in vitro assays [5].…”

Section: Introductionmentioning

confidence: 99%

“…Following preliminary experiments performed on the activity of novel azepane-based inhibitors in cells [5], it was evident that the detection of free oligosaccharides suggested that a number of mannosylated species were generated. These species have been characterised further and support the potential of analysing free oligosaccharides produced as a consequence of inhibition, to delineate pathways of glycoprotein biosynthesis and catabolism.…”

Section: Introductionmentioning

confidence: 99%

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Novel mannosidase inhibitors probe glycoprotein degradation pathways in cells

et al. 2009

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Multiple isoforms of mammalian alpha-mannosidases are active in the pathways of N-linked glycoprotein synthesis and catabolism. They differ in specificity, function and location within the cell and can be selectively inhibited by imino sugar monosaccharide mimics. Previously, a series of structurally related novel 7-membered iminocyclitols were synthesised and found to be inhibitors of alpha-mannosidase using in vitro assays. The present study aimed to delineate alpha-mannosidases hydrolytic pathways in azepane inhibitor treated cells by the analysis of free oligosaccharides (FOS) as markers of endoplasmic reticulum (ER), Golgi, lysosomal and cytosolic alpha-mannosidase activities. Two compounds were identified as potent and selective cytosolic alpha-mannosidase inhibitors. Two related compounds were shown to be potent inhibitors of lysosomal alpha-mannosidase with different potencies towards alpha1,6 mannosidase. The specificities of these novel 7-membered imino sugars are related to differences in their structure and D: -mannose-like stereochemistry. Specific ER-mannosidase inhibition by kifunensine also reveals significant non-proteasomal degradation following FOS analysis and appears to be cell line dependent. The availability of more selective inhibitors allows the pathways of N-linked oligosaccharide metabolism to be dissected.

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“…Water was Milli-Q™ grade. Non-alkylated parent compounds of inhibitors 1-4, were N-butylated and purified as described [5]. The structures are shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…These were found to be potent ß-glucosidase inhibitors with weak activity towards α-glucosidases and α-mannosidases using in vitro assays [5].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel mannosidase inhibitors probe glycoprotein degradation pathways in cells

et al. 2009

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“…[212] Finally, BlØriot and co-workers recently reported moderately active azepane-based inhibitors of GCS (57)(58)(59)(60). [213] …”

Section: Inhibitors Of Glucosylceramide Synthasementioning

confidence: 98%

Glycosphingolipids—Nature, Function, and Pharmacological Modulation

et al. 2009

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The discovery of the glycosphingolipids is generally attributed to Johan L. W. Thudichum, who in 1884 published on the chemical composition of the brain. In his studies he isolated several compounds from ethanolic brain extracts which he coined cerebrosides. He subjected one of these, phrenosin (now known as galactosylceramide), to acid hydrolysis, and this produced three distinct components. One he identified as a fatty acid and another proved to be an isomer of D-glucose, which is now known as D-galactose. The third component, with an "alkaloidal nature", presented "many enigmas" to Thudichum, and therefore he named it sphingosine, after the mythological riddle of the Sphinx. Today, sphingolipids and their glycosidated derivatives are the subjects of intense study aimed at elucidating their role in the structural integrity of the cell membrane, their participation in recognition and signaling events, and in particular their involvement in pathological processes that are at the basis of human disease (for example, sphingolipidoses and diabetes type 2). This Review details some of the recent findings on the biosynthesis, function, and degradation of glycosphingolipids in man, with a focus on the glycosphingolipid glucosylceramide. Special attention is paid to the clinical relevance of compounds directed at interfering with the factors responsible for glycosphingolipid metabolism.

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Glycosphingolipide – Natur, Funktion und pharmakologische Modulierung

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et al. 2009

Angewandte Chemie

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Die Entdeckung der Glycosphingolipide wird im Allgemeinen Johan L. W. Thudichum zugeschrieben, der 1884 über die chemische Zusammensetzung des Gehirns publizierte. In seinen Studien isolierte er aus ethanolischen Hirnextrakten mehrere Verbindungen, die er als Cerebroside bezeichnete. Eine dieser Verbindungen, Phrenosin (heute als Galactosylceramid bekannt), unterwarf er einer sauren Hydrolyse, aus der drei Komponenten hervorgingen. Eine Komponente identifizierte er als Fettsäure, eine andere als Isomer zur D‐Glucose, heute als D‐Galactose bekannt. Die dritte Komponente mit “alkaloidaler Natur” gab Thudichum “viele Rätsel” auf, weshalb er sie Sphingosin nannte, nach dem mythologischen Rätsel der Sphinx. Derzeit sind Sphingolipide und ihre glycosidierten Derivate Gegenstand intensiver Forschung mit dem Ziel, ihre Funktion für die strukturelle Integrität der Zellmembran, ihre Teilnahme in Erkennungs‐ und Signalübertragungsvorgängen und besonders ihre Beteiligung an pathologischen Prozessen, die als Ursache menschlicher Krankheiten (z. B. von Sphingolipidosen und Typ‐2‐Diabetes) gelten, aufzuklären. Dieser Aufsatz wird auf neuere Befunde zur Biosynthese, Funktion und zum Abbau von Glycosphingolipiden im Menschen eingehen, mit Fokus auf das Glycosphingolipidglucosylceramid. Besondere Aufmerksamkeit richtet sich auf die klinische Bedeutung von Verbindungen, die mit den Faktoren des Glycosphingolipid‐Metabolismus wechselwirken.

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New Synthetic Seven‐Membered 1‐Azasugars Displaying Potent Inhibition Towards Glycosidases and Glucosylceramide Transferase

Cited by 52 publications

References 60 publications

Novel mannosidase inhibitors probe glycoprotein degradation pathways in cells

Novel mannosidase inhibitors probe glycoprotein degradation pathways in cells

Glycosphingolipids—Nature, Function, and Pharmacological Modulation

Glycosphingolipide – Natur, Funktion und pharmakologische Modulierung

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