Synthesis of New Sialidase Inhibitors, 6‐Amino‐6‐Deoxysialic Acids

Baumberger, Franz; Vasella, Andrea; Schauer, Roland

doi:10.1002/hlca.19880710216

Cited by 48 publications

(11 citation statements)

References 82 publications

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“…tested them for V. cholerae sialidase with 4-nitrothiophenyl-NeuSAc as substrate. The values are also higher than the K^ values found by Baumberger, Vasella and Schauer [41] for synthetic 6-amino-6-deoxysialic acids with the same substrate (methylumbelliferyl-NeuSAc) and V. cholerae sialidase as enzyme. Modification in the neuraminic acid part is obviously more important with regard to inhibitory potency of the molecule than the stability of the ketosidic bond against enzyme hydrolysis of potential substrates like the α-thioketosides.This is supported by the fact that A 7 -acyl-2-deoxy-2,3-dehydroneuraminic acids are the best inhibitors of sialidases^.…”

Section: Resultscontrasting

confidence: 62%

Phase-Transfer-Catalysed Synthesis of N-Acetylneuraminic Acid α-Thioketosides and Inhibitor Studies withClostridium perfringensSialidase

Rothermel¹,

Faillard²

1989

Biological Chemistry Hoppe-Seyler

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The -thioketosides of methyl 5-acetamido-4,7,8,9-tetra-O-acetylneuraminate with thioacetic acid, thiophenol, 4-nitrothiophenol, 4-aminothiophenol, 2-mercaptopyridin and mercaptobenzothiazol as aglycones were synthesized by phase-transfer catalysis in good yields. The methyl 5-acetamido-4,7,8,9-tetra-<9-acetyl-2-thioacetylneuraminate is the analogous thio compound to the methyl 5-acetamido-2,4,7,8,9-penta-O-acetylneuraminate and can be used as intermediate for preparing S-ketosides of NeuSAc. By Zemplen saponification and mild hydrolysis of the methyl-ester group the free Neu5Ac-a-thioketosides with thiophenol, 4-nitrothiophenol, 4-aminothiophenol and 2-mercaptopyridin could be prepared. These ketosides were found to be inhibitors of C. perfringens sialidase with K-values between 2.3mM and 6.6mM. The free Neu5Ac-a-mercaptobenzothiazolyl ketoside could not be prepared by this procedure. It was completely hydrolysed during Zemplen saponification and methyl-ester hydrolysis in alkaline medium. Phasen-Tmnsfer-katalysierte Synthese von N-Acetylneuraminsäure a-thioketosiden und Inhibitor-Studien mit Clostridium-perfringens-SialidaseZusammenfassung: Die -Thioketoside des 4,7,8,9-Tetra-O-acetyl-TV-acetylneuraminsäure-methylesters mit Thioessigsäure, Thiophenol, 4-Nitrothiophenol, 4-Aminothiophenol, 2-Mercaptopyridin und Mercaptobenzothiazol als Aglycone wurden mittels PhasenTransferkatalyse in guten Ausbeuten darstellt. Der 2-Thioacetyl-4,7,8,9-tetra-O-acetyK/V-acetylneuraminsäure-methylester ist das Thio-Analogon des W-Acetyl-2,4,7,8,9-penta-0-acetylneuraminsäure-methylesters und kann als Zwischenverbindung zur Darstellung von S-Ketosiden der NeuSAc verwendet werden. Durch Zemplen-und milde Hydrolyse des Methylesters konnten die freien Neu5Ac--Thioketoside mit Thiophenol, 4-Nitro thiophenol, 4-Aminothiophenol und 2-Mercaptopyridin dargestellt werden. Sie wurden als Sialidase-Inhibitoren für C.-perfringens-Sialidase getestet. Es wurden K { -Werte von 6.6mM (Thiophenyl-Neu5Ac), 4.1mM (4-Aminothiophenyl-Neu5Ac), 2.5mM (2'-Mercaptopyridyl-NeuSAc) und 2.3mM (4-NitrothiophenylNeuSAc) ermittelt. Das freie Mercaptobenzothiazolyl-a-Neu5Ac-ketosid konnte nicht dargestellt werden, da unter den alkalischen Bedingungen der Zemplen-und Methylester-Hydrolyse eine vollstän-dige Ketosidspaltung erfolgte.

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Section: Resultscontrasting

confidence: 62%

Phase-Transfer-Catalysed Synthesis of N-Acetylneuraminic Acid α-Thioketosides and Inhibitor Studies withClostridium perfringensSialidase

Rothermel¹,

Faillard²

1989

Biological Chemistry Hoppe-Seyler

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“…5,7,8, 4.11 (dd,l H ,),4.19 (dd,l H ,2H,4.87 (ddd,l H ,5.11 (s,l H ,2H,NH, 6 = 160.78, 157.08, 154.49, 152.04, 125.42, 116.00, 115.78, 113.62, 107.25, 18.61; signals of the sialic acid moiety: 6 = 171. 14,170.53 (2 C=O),170.46,170.24,167.71 (together 6 C=O),76.30,70.23,[2][3][4][5][6][7]20.80,20.71 (OCOCH3) 5,7,8,9Acsl 3H,2.76 (dd,1 H,,), 3.81 (s, 3H, COOCH3), 4.12 (ddd,l H ,4.36 (d,l H ,4.45 (dd,l H ,4.54 (dd,IH,5.06 (ddd,l H ,2H,5.72 (d,1 H,NH), 6.25 (s, 1 H,7.11 (d,1 H,7.14 (dd,l H ,…”

Section: Methodsmentioning

confidence: 99%

Structural Variations of N‐Acetylneuraminic Acid, 11, Synthesis of the 4‐Methylumbelliferyl 2α‐Glycosides of 7‐Epi‐, 8‐Epi‐, and 7,8‐Bis(epi)‐N‐acetylneuraminic Acids, as well as of 7‐Deoxy‐, 8‐Deoxy‐, 9‐Deoxy‐, and 4,7‐Dideoxy‐N‐acetylneuraminic Acids and Their Behaviour Towards Sialidase from Vibrio cholerae

et al. 1989

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Sialic acids as terminal units of the oligosaccharide chains of numerous glycoproteins and glycolipids are involved in many biologically important function^',^). The amount of sialic acids important for the function of these molecules +) On study leave from the Department of Chemistry, Shivaji Uniresults from a balance between the incorporation of an activated sialic acid into a matrix and its release by sialidases. In order to gain more insight into the structural requirements for the activity of these enzymes, many non-natural sialic acids have been prepared over the last years. Structural variations have been performed at C-g4) and C-45-7) and evaluated with respect to their activation by CMP-sialate versity,

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“…Part). A similar resistance of a benzylidene group has been noted, e.g., by Baumberger et al [27]. The complex 'H-NMR spectrum indicates that 32 exists as a mixture of the ketone 32a (CO band of medium intensity at 1732 cm-') and the cyclic tautomer 32b (OH band at 3494 cm-I).…”

Section: ' )mentioning

confidence: 84%

Synthesis of Galactose‐ and N‐Acetylglucosamine‐Derived Tetrazoles and their evaluation as β‐glycosidase inhibitors

Heightman

Ermert

Klein

et al. 1995

Helvetica Chimica Acta

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The title compounds 6 and 7 have been prepared from the known 2,3-di-U -benzyl-4,6-0 -benzylidene-o-galactose (18) and N'-acetyl-tri-O -benzyl-D-glucosamine oxime (29) in eight and six steps, respectively. The azidonitrile leading to the benzylated galacto-tetrazole 16 was prepared from 14 and cyclized under the conditions of its formation (Scheme I). The alcohol 13 was obtained by oxidation of 10 followed by reduction. Better yields and diastereoselectivities were realized, when the benzylidene-protected D-gafacto-alcohol 20 was subjected to oxidoreduction, yielding the L-altro -alcohol 22 via the ketone 21 (Scheme 2). Treatment of the corresponding tosylate 24 with NaN, yielded the tetrazole 25, which was deprotected to 6. The tetrabenzyl ether 16 (from 14, or from 25 via 27) was reduced to 28 and deprotected to give the known deoxygalactostatin 8 (Scheme 2). Oxidation of the hydroxynitrile 30, derived from 29, followed by reduction of 32 yielded mostly the L-ido-hydroxynitrile (Scheme 3), which was tosylated and treated with NaN3 to give the tetrazole 3Sa and its manno-isomer 36a, while AI(N,), yielded (E)-and (2)-38 (Scheme 4). The intermediate azide 39 was isolated besides 40 when NH,N,/DMF was used; thermolysis of 39 gave mostly 3Sa, which was deprotected to 7, besides some elimination product 41. Both 6 and 7 are stable in the pH range 1-10; at pH 12, 6 is unaffected but, 7 shows some epimerization to the manno-configurated isomer 43. The tetrazole 6 is a competitive inhibitor of the P-galactosidases from E. coli (4 = 1 p~, pH 6.8) and bovine liver (4 = 0.8 VM, pH 7.0); the N-acetyl-P-D-glucosaminidase from bovine kidney is competitively inhibited by 7 (4 % 0.2 p~, pH 4.1).Introduction. -We have designed the gluco-tetrazole 1 [I] [2] and its manno-epimer 2 [2] as neutral transition-state analogues for the inhibition of a-glucosidases and p-mannosidases, respectively. These tetrazoles possess a half-chair conformation in the solid state; in solution, 1 is a half-chair t6H7) and 2 a sofa (S7). A detailed kinetic study demonstrated that the inhibition is competitive and configurationally selective, and established these tetrahydrotetrazolopyridines (tetrahydropyridotetrazoles)') as transition-state analogues [2]. The inhibitory properties of the gluco-tetrazole 1 parallel those of D-glucono-l,5-lactone, but, unlike the corresponding lactones, 1 and 2 are stable towards hydrolysis over a wide range of pH values, an advantage for co-crystallization [9] and for their potential use as templates in the generation of catalytic antibodies [lo] [ll]. Additionally, reduction of the tetra-0-benzyl-protected tetrazole 3 is a key step in a new route to deoxynojirimycin [I].Galactose and N-acetylglucosamine derivatives possessing an sp2-hybridized anomeric center, such as galactono-1,5-1actam 4 [I21 and derivatives [ 131, the N-acetylglucosaminolactone 5 [14], the related lactone oximes [14] [15] and the lactam [14], are

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Synthesis of New Sialidase Inhibitors, 6‐Amino‐6‐Deoxysialic Acids

Cited by 48 publications

References 82 publications

Phase-Transfer-Catalysed Synthesis of N-Acetylneuraminic Acid α-Thioketosides and Inhibitor Studies withClostridium perfringensSialidase

Phase-Transfer-Catalysed Synthesis of N-Acetylneuraminic Acid α-Thioketosides and Inhibitor Studies withClostridium perfringensSialidase

Synthesis of Galactose‐ and N‐Acetylglucosamine‐Derived Tetrazoles and their evaluation as β‐glycosidase inhibitors

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