Chemical modification of azasugars, inhibitors of N‐glycoprotein‐processing glycosidases and of HIV‐I infection: Review and structure‐activity relationships

Broek, L. A. G. M. Van Den; Vermaas, D. J.; Heskamp, B. M.; Boeckel, C. A. A. Van; Tan, Min; Bolscher, Jan G. M.; Ploegh, Hidde L.; Kemenade, Folkert J. van; Goede, R. E. Y. De; Miedema, Frank

doi:10.1002/recl.19931120204

Cited by 69 publications

(8 citation statements)

References 81 publications

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“…We either left the secondary nitrogen unmodified (to obtain the respective deoxygenated analogues of the natural product, deoxynojirimycin), introduced a butyl group (enabling comparison with the clinically applied drug, Zavesca), or introduced an adamantanemethyloxypentyl group (to allow a head-to-head comparison with our lead structures, 2 and 3 ). The synthetic schemes through which the compounds are prepared follow well-established literature procedures (see the experimental section for full experimental and analytical details − ). These routes proceed through partially unsaturated piperidine intermediates, and we capitalized on this by also preparing piperidine derivatives A .…”

mentioning

confidence: 99%

Assessment of Partially Deoxygenated Deoxynojirimycin Derivatives as Glucosylceramide Synthase Inhibitors

Berg

Wennekes

Ghisaidoobe

et al. 2011

ACS Med. Chem. Lett.

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Glucosylceramide synthase (GCS) is an approved drug target for the treatment of Gaucher disease and is considered as a valid target for combating other human pathologies, including type 2 diabetes. The clinical drug N-butyldeoxynojirimycin (Zavesca) is thought to inhibit through mimicry of its substrate, ceramide. In this work we demonstrate that, in contrast to what is proposed in this model, the C2-hydroxyl of the deoxynojirimycin core is important for GCS inhibition. Here we show that C6-OH appears of less important, which may set guidelines for the development of GCS inhibitors that have less affinity (in comparison with Zavesca) for other glycoprocessing enzymes, in particular those hydrolases that act on glucosylceramide.

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mentioning

confidence: 99%

Assessment of Partially Deoxygenated Deoxynojirimycin Derivatives as Glucosylceramide Synthase Inhibitors

Berg

Wennekes

Ghisaidoobe

et al. 2011

ACS Med. Chem. Lett.

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“…This is an advancement on the published literature where synthesis of 4f required additional steps to functionalised DMJ. 80 While mass corresponding to iodo aminoglycoside 99 was observed via HRMS of the acidic reaction mixture, consistent with the observations the synthesis of derivatives 4b-4e, only the desired azasugar was observed via TLC, HRMS, and 1 H NMR of the crude reaction products or during purification. It was envisioned that the furanose 100, analogous to 94 (section 2.4.1) may have been observed in keeping with the structural similarity of the benzylamine to 2phenylethylamine used for the synthesis of 4e however, this was not isolated.…”

Section: The Synthesis Of N-benzyl-dmjsupporting

confidence: 84%

The efficient synthesis of 1-deoxymannojirimycin and its derivatives

Deeble¹

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<p>Azasugars are structural analogues of carbohydrates whereby the oxygen in the heterocyclic ring is substituted for a nitrogen. These carbohydrates are an important class of compounds with medicinal bioactivities and have shown potential for the treatment of diabetes, viral-infection, cancers, and lysosomal storage diseases. 1-deoxymannojirimycin (DMJ), is a mannosidase inhibiting azasugar which has shown anti-cancer and anti-viral activity. There has been significant effort put towards developing methodology to produce this compound and libraries of its derivatives. This thesis presents the synthesis of DMJ and a selection of its derivatives via an efficient 4 step methodology from a carbohydrate starting material, exploiting chemo and regioselective reactions to allow for a total synthesis with minimal use of protecting groups. The synthesis of DMJ, using the methodology developed herein, surpasses published syntheses in efficiency. This synthetic strategy was then used for the preparation of N-functionalised DMJ derivatives without the requirement of additional synthetic steps. To illustrate the versatility of this methodology, a selection of derivatives incorporating different functionalities have been synthesised.</p>

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“…Our approach was to use compound 14 , the simplest available L ‐iduronic‐acid building block, which is useful as an acceptor and is easily transformable into a donor, in two well‐established procedures, which have been elaborated for the 3‐ O ‐benzyl‐counterpart,5b, 18 for the synthesis. L ‐Idose derivative 10 19 was prepared from D ‐glucose by using the C‐5‐epimerization method 5b. Acid hydrolysis of epoxide 10 resulted in 3‐ O ‐methyl‐ L ‐idose, which was treated with benzaldehyde in the presence of trifluoroacetic acid (TFA)18 to give compound 11 with an α/β‐anomeric ratio of about 1:2.…”

Section: Resultsmentioning

confidence: 99%

“…The common trisaccharide part of the two target compounds was constructed from l-iduronic acid and two monosaccharide sulfonic acids, thus demonstrating that sulfonic-ester-containing glycosides could serve as excellent building blocks in oligosaccharide synthesis, both as donors or acceptors. Pentasaccharide disulfonic acid 3 was obtained from a [2+3] block synthesis by utilizing trisaccharide acceptor 18 and a glucuronide disaccharide donor (19). However, this approach was low-yielding, owing to the low reactivity of the uronic-acid-containing donor (19).…”

Section: Discussionmentioning

confidence: 99%

“…Pentasaccharide disulfonic acid 3 was obtained from a [2+3] block synthesis by utilizing trisaccharide acceptor 18 and a glucuronide disaccharide donor (19). However, this approach was low-yielding, owing to the low reactivity of the uronic-acid-containing donor (19). Elongation of trisaccharide acceptor 18 with a non-oxidized precursor of the glucuronic acid, followed by post-glycosidation oxidation at a tetrasaccharide level and a subsequent [1+4] coupling reaction, was a highly efficient strategy that resulted in trisulfonic acid pentasaccharide 4.…”

Section: Discussionmentioning

confidence: 99%

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Synthesis and Anticoagulant Activity of Bioisosteric Sulfonic‐Acid Analogues of the Antithrombin‐Binding Pentasaccharide Domain of Heparin

Herczeg

Lázár

Bereczky

et al. 2012

Chemistry A European J

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Two pentasaccharide sulfonic acids that were related to the antithrombin-binding domain of heparin were prepared, in which two or three primary sulfate esters were replaced by sodium-sulfonatomethyl moieties. The sulfonic-acid groups were formed on a monosaccharide level and the obtained carbohydrate sulfonic-acid esters were found to be excellent donors and acceptors in the glycosylation reactions. Throughout the synthesis, the hydroxy groups to be methylated were masked in the form of acetates and the hydroxy groups to be sulfated were masked with benzyl groups. The disulfonic-acid analogue was prepared in a [2+3] block synthesis by using a trisaccharide disulfonic acid as an acceptor and a glucuronide disaccharide as a donor. For the synthesis of the pentasaccharide trisulfonic acid, a more-efficient approach, which involved elongation of the trisaccharide acceptor with a non-oxidized precursor of the glucuronic acid followed by post-glycosidation oxidation at the tetrasaccharide level and a subsequent [1+4] coupling reaction, was elaborated. In vitro evaluation of the anticoagulant activity of these new sulfonic-acid derivatives revealed that the disulfonate analogue inhibited the blood-coagulation-proteinase factor Xa with outstanding efficacy; however, the introduction of the third sulfonic-acid moiety resulted in a notable decrease in the anti-Xa activity. The difference in the biological activity of the disulfonic- and trisulfonic-acid counterparts could be explained by the different conformation of their L-iduronic-acid residues.

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Chemical modification of azasugars, inhibitors of N‐glycoprotein‐processing glycosidases and of HIV‐I infection: Review and structure‐activity relationships

Cited by 69 publications

References 81 publications

Assessment of Partially Deoxygenated Deoxynojirimycin Derivatives as Glucosylceramide Synthase Inhibitors

Assessment of Partially Deoxygenated Deoxynojirimycin Derivatives as Glucosylceramide Synthase Inhibitors

The efficient synthesis of 1-deoxymannojirimycin and its derivatives

Synthesis and Anticoagulant Activity of Bioisosteric Sulfonic‐Acid Analogues of the Antithrombin‐Binding Pentasaccharide Domain of Heparin

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