Synthesis of β-d-galactofuranosyl nucleoside analogues. A new type of β-d-galactofuranosidase inhibitor (original) (raw)
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1-Thio- -D-galactofuranosides: synthesis and evaluation as -D-galactofuranosidase inhibitors
Glycobiology, 1998
β-D-galactofuranosidase is a good chemotherapeutic target for the design of inhibitors, since β-D-galactofuranose is a constituent of important parasite glycoconjugates but is not present in the host mammals. With this aim, we have synthesized for the first time alkyl, benzyl and aryl 1-thio-β-D-galactofuranosides by condensation of penta-O-benzoyl-α,β-D-galactofuranose with the corresponding thiols, in the presence of SnCl 4 as catalyst. The complete chemical and spectroscopical characterization of these compounds showed that the reaction was stereoselective. Debenzoylation with sodium methoxide afforded the β-S-galactofuranosides in high yield. The thioglycosides were tested as inhibitors of the β-D-galactofuranosidase of Penicillium fellutanum, using for the first time 4-nitrophenyl-β-D-galactofuranoside as chromogenic substrate. The 4-aminophenyl-1-thio-β-D-galactofuranoside, obtained by catalytic hydrogenation of the nitrophenyl derivative, was the best inhibitor being then an adequate ligand for the preparation of an affinity phase aimed at the isolation of β-D-galactofuranosidases from different sources. Also the inhibitory activity of D-galactono-1,4-lactone was shown.
1-Thio-β-D-galactofuranosides: synthesis and evaluation as β-D-galactofuranosidase inhibitors
2 To whom correspondence should be addressed β-D-galactofuranosidase is a good chemotherapeutic target for the design of inhibitors, since β-D-galactofuranose is a constituent of important parasite glycoconjugates but is not present in the host mammals. With this aim, we have synthesized for the first time alkyl, benzyl and aryl 1-thio-β-D-galactofuranosides by condensation of penta-O-benzoyl-α,β-D-galactofuranose with the corresponding thiols, in the presence of SnCl 4 as catalyst. The complete chemical and spectroscopical characterization of these compounds showed that the reaction was stereoselective. Debenzoylation with sodium methoxide afforded the β-S-galactofuranosides in high yield. The thioglycosides were tested as inhibitors of the β-D-galactofuranosidase of Penicillium fellutanum, using for the first time 4-nitrophenyl-β-D-galactofuranoside as chromogenic substrate. The 4-aminophenyl-1-thio-β-D-galactofuranoside, obtained by catalytic hydrogenation of the nitrophenyl derivative, was the best inhibitor being then an adequate ligand for the preparation of an affinity phase aimed at the isolation of β-D-galactofuranosidases from different sources. Also the inhibitory activity of D-galactono-1,4-lactone was shown.
Bioorganic & Medicinal Chemistry, 2013
A new (1?6)-linked thiodisaccharide formed by two galactofuranosyl units has been synthesized. Methyl (methyl a,b-D-galactofuranosid)uronate was employed as the starting compound, which was per-O-silylated with TBSCl and reduced with LiAlH 4 to afford methyl 2,3,5-triO -tert-butyldimethylsilyl-b-D-galactofuranoside (2b) as a key precursor for the preparation of methyl per-O-tert-butyldimethylsilyl-6-thio-b-D-galactofuranoside (12). The free thiol group of 12 was glycosylated and the product O-deprotected to afford the target b-D-Galf-S-(1?6)-b-D-Galf-OMe (14). The conformations of this thiodisaccharide were preliminarily studied using combined theoretical calculations and NMR data. Furthermore, the glycomimetic 14 showed to be a competitive inhibitor of the b-galactofuranosidase from Penicillum fellutanum (K i = 3.62 mM).
Zenodo (CERN European Organization for Nuclear Research), 2008
The title compounds were prepared by the condensation of tetra-0-acetyi-P-o-galactopyranosyl isothiocyanate with several amines, 2-aminobenzothiazole/substituted benzothiazoles and alcohols respectively. The structure of these new N-galactoside has been established on the basis of usual chemical transformations and IR, NMR and Mass spectral studies of some typical cases. Keywotds : N-Galactosides, galactosyl isothiocyanate, galactosyl thiocarbamides, galactosyl benzothiazolyl thiocarbamides, galactosyl thiocarbamates.
N-Alkyl-, 1-C-Alkyl-, and 5-C-Alkyl-1,5-dideoxy-1,5-imino-(l)-ribitols as Galactosidase Inhibitors
ChemMedChem, 2016
A series of 1,5-dideoxy-1,5-imino-(l)-ribitol (DIR) derivatives carrying alkyl or functionalized alkyl groups were prepared and investigated as glycosidase inhibitors. These compounds were designed as simplified 4-epi-isofagomine (4-epi-IFG) mimics and were expected to behave as selective inhibitors of β-galactosidases. All compounds were indeed found to be highly selective for β-galactosidases versus α-glycosidases, as they generally did not inhibit coffee bean α-galactosidase or other α-glycosidases. Some compounds were also found to be inhibitors of almond β-glucosidase. The N-alkyl DIR derivatives were only modest inhibitors of bovine β-galactosidase, with IC50 values in the 30-700 μm range. Likewise, imino-l-ribitol substituted at the C1 position was found to be a weak inhibitor of this enzyme. In contrast, alkyl substitution at C5 resulted in enhanced β-galactosidase inhibitory activity by a factor of up to 1000, with at least six carbon atoms in the alkyl substituent. Remarka...
Carbohydrate Research, 2012
The use of the easily available persilylated derivative 1 for the synthesis of C-and S-Galf derivatives has been investigated. By anomeric iodination of 1 with TMSI, followed by in situ coupling with C-and S-nucleophiles under very mild conditions and in the absence of promoters, derivatives with value as glycomimetics or as precursors of glycobiological tools were synthesized. Among them, the synthesis of the isolable 1-galactofuranosylthiol 15 is remarkable, as it paves the way for alternative approaches for S-galactofuranosyl derivatives.
Bioorganic & Medicinal Chemistry, 2009
Thiodisaccharides having b-D-Galf or a-L-Araf units as non-reducing end have been synthesized by the SnCl 4-or MoO 2 Cl 2-promoted thioglycosylation of per-O-benzoyl-D-galactofuranose (1), its 1-O-acetyl analogue 4, or per-O-acetyl-a-L-arabinofuranose (16) with 6-thioglucose or 6-thiogalactose derivatives. After convenient removal of the protecting groups, the free thiodisaccharides having the basic structure b-D-Galf(1?6)-6-thio-aD -Glcp-OMe (5) or b-D-Galf(1?6)-6-thio-aD -Galp-OMe (15) were obtained. The respective a-L-Araf analogues 18 and 20 were prepared similarly from 16. Alternatively, b-D-Galf(1?4)-4thio-3-deoxy-a-L-Xylp-OiPr was synthesized by Michael addition to a sugar enone of 1-thio-b-D-Galf derivative, generated in situ from the glycosyl isothiourea derivative of 1. The free S-linked disaccharides were evaluated as inhibitors of the b-galactofuranosidase from Penicillium fellutanum, being 15 and 20 the more active inhibitors against this enzyme.
Bioorganic Medicinal Chemistry, 2009
Thiodisaccharides having b-D-Galf or a-L-Araf units as non-reducing end have been synthesized by the SnCl 4-or MoO 2 Cl 2-promoted thioglycosylation of per-O-benzoyl-D-galactofuranose (1), its 1-O-acetyl analogue 4, or per-O-acetyl-a-L-arabinofuranose (16) with 6-thioglucose or 6-thiogalactose derivatives. After convenient removal of the protecting groups, the free thiodisaccharides having the basic structure b-D-Galf(1?6)-6-thio-aD -Glcp-OMe (5) or b-D-Galf(1?6)-6-thio-aD -Galp-OMe (15) were obtained. The respective a-L-Araf analogues 18 and 20 were prepared similarly from 16. Alternatively, b-D-Galf(1?4)-4thio-3-deoxy-a-L-Xylp-OiPr was synthesized by Michael addition to a sugar enone of 1-thio-b-D-Galf derivative, generated in situ from the glycosyl isothiourea derivative of 1. The free S-linked disaccharides were evaluated as inhibitors of the b-galactofuranosidase from Penicillium fellutanum, being 15 and 20 the more active inhibitors against this enzyme.