2771-48-4Relevant articles and documents
An improved procedure for the analysis of linkage positions in 2- acetamido-2-deoxy-D-glucopyranosyl residues by the reductive-cleavage method
D'Ambra,Gray
, p. 115 - 125 (1994)
The conditions of the reductive-cleavage method were modified to allow simultaneous analysis of 2-acetamido-2-deoxy-D-glucopyranosyl residues and monosaccharides of other classes. Methyl 2-deoxy-3,4,6-tri-O-methyl-2-(N- methylacetamido)-β-D-glucopyranoside was found to undergo transglycosidation under reductive-cleavage conditions when the reaction was quenched with an alcohol. Transglycosidation proceeded via an oxazolinium-ion intermediate, which then acted as a glycosyl donor to form an anomerically pure product. Time-course studies showed that in the presence of trimethylsilyl trifluoromethanesulfonate (Me3SiOSO2CF3), 4 h were required for complete conversion of the substrate into this intermediate, which was then trapped with methanol-d4. When the reaction was conducted in the presence of a mixture of trimethylsilyl methanesulfonate (Me3SiOSO2Me) and boron trifluoride etherate (BF3·OEt2) or with BF3·OEt2 alone, 24 h and 48 h, respectively, were required for complete conversion. The α anomer was unreactive after 24 h under all conditions, confirming earlier results. Reaction with racemic 2-butanol yielded a pair of diastereomers, in a 1:1 ratio, which were distinguishable by their GLC retention times and their 1H NMR spectra. Reaction with (S)-2-butanol gave only one of the diastereomeric products. These experiments demonstrated the feasibility of using the reductive-cleavage method to determine the absolute configuration of 2- acetamido sugars. The condition of the reductive-cleavage method were modified to allow simultaneous analysis of 2-acetamido-2-deoxy-D-glycopyranosyl residues and monosaccharides. These experiments demonstrated the feasibility of using the reductive-cleavage method to determine the absolute configuration of 2-acetamido sugars.
Analysis of PUGNAc and NAG-thiazoline as transition state analogues for human O-GlcNAcase: Mechanistic and structural insights into inhibitor selectivity and transition state poise
Whitworth, Garrett E.,Macauley, Matthew S.,Stubbs, Keith A.,Dennis, Rebecca J.,Taylor, Edward J.,Davies, Gideon J.,Greig, Ian R.,Vocadlo, David J.
, p. 635 - 644 (2007)
O-GlcNAcase catalyzes the cleavage of β-O-linked 2-acetamido-2-deoxy- β-D-glucopyranoside (O-GlcNAc) from serine and threonine residues of post-translationally modified proteins. Two potent inhibitors of this enzyme are O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) and 1,2-dideoxy-2′-methyl-α-D-glucopyranoso[2,1-d]-Δ2′- thiazoline (NAG-thiazoline). Derivatives of these inhibitors differ in their selectivity for human O-GlcNAcase over the functionally related human lysosomal β-hexosamindases, with PUGNAc derivatives showing modest selectivities and NAG-thiazoline derivatives showing high selectivities. The molecular basis for this difference in selectivities is addressed as is how well these inhibitors mimic the O-GlcNAcase-stabilized transition state (TS). Using a series of substrates, ground state (GS) inhibitors, and transition state mimics having analogous structural variations, we describe linear free energy relationships of log(KM/kcat) versus log(KI) for PUGNAc and NAG-thiazoline. These relationships suggest that PUGNAc is a poor transition state analogue, while NAG-thiazoline is revealed as a transition state mimic. Comparative X-ray crystallographic analyses of enzyme-inhibitor complexes reveal subtle molecular differences accounting for the differences in selectivities between these two inhibitors and illustrate key molecular interactions. Computational modeling of species along the reaction coordinate, as well as PUGNAc and NAG-thiazoline, provide insight into the features of NAG-thiazoline that resemble the transition state and reveal where PUGNAc fails to capture significant binding energy. These studies also point to late transition state poise for the O-GlcNAcase catalyzed reaction with significant nucleophilic participation and little involvement of the leaving group. The potency of NAG-thiazoline, its transition state mimicry, and its lack of traditional transition state-like design features suggest that potent rationally designed glycosidase inhibitors can be developed that exploit variation in transition state poise.
Chemoenzymatic Synthesis of Glycoconjugates Mediated by Regioselective Enzymatic Hydrolysis of Acetylated 2-Amino Pyranose Derivatives
Zheng, Changping,Bavaro, Teodora,Tengattini, Sara,Mascherpa, Andrea Gualla,Sollogoub, Matthieu,Zhang, Yongmin,Terreni, Marco
supporting information, p. 3622 - 3631 (2019/06/17)
Highly regioselective deprotection of a series of 2-amino pyranose building blocks was achieved by enzymatic hydrolysis. These monodeprotected intermediates were successfully used in the synthesis of a variety of glycoconjugate derivatives with a core of glucosamine or galactosamine, including neo-glycoproteins and glycosphingolipids. The hydrolysis catalyzed by acetylxylan esterase from Bacillus pumilus (AXE) is suitable for the synthesis of neo-glycoproteins with an N-acetyl glucosamine core. The hydrolysis catalyzed by Candida rugosa lipase (CRL) was successfully applied in the preparation of new sialylated glycolipids starting from glucosamine building blocks protected as phthalimide. This chemoenzymatic approach can be used for the preparation of new glycoconjugate products with anticancer activity.
Nucleophilic Aromatic Substitution (SNAr) as an Approach to Challenging Carbohydrate-Aryl Ethers
Henderson, Alexander S.,Medina, Sandra,Bower, John F.,Galan, M. Carmen
, p. 4846 - 4849 (2015/10/12)
A general and practical route to carbohydrate-aryl ethers by nucleophilic aromatic substitution (SNAr) is reported. Upon treatment with KHMDS, C-O bond formation occurs between carbohydrate alcohols and a diverse range of fluorinated (hetero)ar
Direct glycosylation of unprotected and unactivated sugars using bismuth nitrate pentahydrate
Polanki, Innaiah K.,Kurma, Siva H.,Bhattacharya, Asish K.
, p. 196 - 205 (2015/06/08)
Bi(NO3)3, a low-cost, mild, and environmentally green catalyst, has been successfully utilized for Fischer glycosylation for the synthesis of alkyl/aryl glycopyranosides by reacting unprotected sugars, namely, D-glucose, L-rhamnose, D-galactose, D-arabinose, and N-acetyl-D-glucosamine with various alcohols in good to excellent yields. The glycosides were formed with high α-selectivity. Further, an expedient separation of α- and β-glycosides using silver nitrate-impregnated silica gel flash liquid chromatography has been developed.
Probing synergy between two catalytic strategies in the glycoside hydrolase O-GlcNAcase using multiple linear free energy relationships
Greig, Ian R.,Macauley, Matthew S.,Williams, Ian H.,Vocadlo, David J.
supporting information; experimental part, p. 13415 - 13422 (2010/01/16)
Human O-GlcNAcase plays an important role in regulating the post-translational modification of serine and threonine residues with β-O-linked N-acetylglucosamine monosaccharide unit (O-GlcNAc). The mechanism of O-GlcNAcase involves nucleophilic participation of the 2-acetamido group of the substrate to displace a glycosidically linked leaving group. The tolerance of this enzyme for variation in substrate structure has enabled us to characterize O-GlcNAcase transition states using several series of substrates to generate multiple simultaneous free-energy relationships. Patterns revealing changes in mechanism, transition state, and rate-determining step upon concomitant variation of both nucleophilic strength and leaving group abilities are observed. The observed changes in mechanism reflect the roles played by the enzymic general acid and the catalytic nucleophile. Significantly, these results illustrate how the enzyme synergistically harnesses both modes of catalysis; a feature that eludes many small molecule models of catalysis. These studies also suggest the kinetic significance of an oxocarbenium ion intermediate in the O-GlcNAcase-catalyzed hydrolysis of glucosaminides, probing the limits of what may be learned using nonatomistic investigations of enzymic transition-state structure and offering general insights into how the superfamily of retaining glycoside hydrolases act as efficient catalysts.
Iminosugar glycoconjugates
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Page/Page column 5, (2008/06/13)
The iminosugar conjugates according to the invention are N-alkylated 1,5-dideoxy-1,5-iminohexitol or 1,5-dideoxy-1,5-iminopentitol derivatives. The iminosugar component can be, for example, D-gluco-, L-ido-, D-galacto-, D-manno-, 2-acetamido-2-deoxy-D-gluco- or xylo-configuration. The N-substituent is a protected L-α-aminoacid derivative, showing L-lysine-like structural features. The linkage between the carbohydrate and the peptide component is not via the usual glycosidic position, but shows structural features of a very stable tertiary amine. Thus the linkage is very stable. These new compounds are synthesised by using catalytic intramolecular reductive amination of dicarbonyl sugars with partially protected amino acids. The process of intramolecular reductive amination itself is carried out using Pearlman's catalyst (Pd(OH)2/C) and H2 at ambient pressure and room temperature. The resulting accessible class of iminosugar conjugate compounds is represented by the general structure shown in Figure 4(c). The alkyl chain length parameter n can be freely chosen from n=0 upwards. Preferably n is between 0 and 10, and more preferably n is 2, 3, or 4. Residue R1 can be chosen from H, OH, or NHAc, with Ac being Acetyl. R2 can be H, OH, or NHAc. R3, R4, R5, R6 can be H or OH. R7 and R8 can be H, CH2OH CH3, COQH, or COOR with R being Alkyl or Aryl. R9 and R10 can be chosen from H, NH2, NHR, with R being a protective group, an amino acid, a peptide, or a protein. R11 can be OH, O-Alkyl, O-Aryl, NH2, N-Alkyl, N-Aryl, amino acid or peptide, connected via an amide bond.
Mild and efficient method for the cleavage of benzylidene acetals using HClO4-SiO2 and direct conversion of acetals to acetates
Agnihotri, Geetanjali,Misra, Anup Kumar
, p. 3653 - 3658 (2007/10/03)
HClO4-SiO2 has been used successfully for the deprotection of benzylidene acetals and the direct conversion of benzylidene acetals to the corresponding di-O-acetates. The reactions are very fast and yields are excellent.
Synthetic Peptidoglycan Substrates for Penicillin-Binding Protein 5 of Gram-Negative Bacteria
Hesek, Dusan,Suvorov, Maxim,Morio, Ken-Ichiro,Lee, Mijoon,Brown, Stephen,Vakulenko, Sergei B.,Mobashery, Shahriar
, p. 778 - 784 (2007/10/03)
The major constituent of the bacterial cell wall, peptidoglycan, is comprised of repeating units of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) with an appended peptide. Penicillin-binding proteins (PBPs) are involved in the final stages of bacterial cell wall assembly. Two activities for PBPs are the cross-linking of the cell wall, carried out by DD-transpeptidases, and the DD-peptidase activity, that removes the terminal D-Ala residue from peptidoglycan. The DD-peptidase activity moderates the extent of the cell wall cross-linking. There exists a balance between the two activities that is critical for the well-being of bacterial cells. We have cloned and purified PBP5 of Escherichia coli. The membrane anchor of this protein was removed, and the enzyme was obtained as a soluble protein. Two fragments of the polymeric cell wall of Gram-negative bacteria (compounds 5 and 6) were synthesized. These molecules served as substrates for PBP5. The products of the reactions of PBP5 and compounds 5 and 6 were isolated and were shown to be D-Ala and the fragments of the substrates minus the terminal D-Ala. The kinetic parameters for these enzymic reactions were evaluated. PBP5 would appear to have the potential for turnover of as many as 1.4 million peptidoglycan strands within a single doubling time (i.e., generation) of E. coli.
Furanodictine A and B: Amino sugar analogues produced by cellular slime mold Dictyostelium discoideum showing neuronal differentiation activity
Kikuchi,Saito,Komiya,Takaya,Honma,Nakahata,Ito,Oshima
, p. 6982 - 6987 (2007/10/03)
We investigated the constituents of Dictyostelium discoideum to clarify the diversity of secondary metabolites of Dictyostelium cellular slime molds and to explore biologically active substances that could be useful in the development of novel drugs. From a methanol extract of the multicellular fruit body of D. discoideum, we isolated two novel amino sugar analogues, furanodictine A (1) and B (2). They are the first 3,6-anhydrosugars to be isolated from natural sources. Their relative structures were elucidated by spectral means, and the absolute configurations were confirmed by asymmetric syntheses of 1 and 2. These furanodictines potently induce neuronal differentiation of rat pheochromocytoma (PC-12) cells.
