Biomedical subjects
Publications and source records attributed to Robert A Field.
Perchloric acid immobilised on silica gel has been used as an efficient promoter for per-O-acetylation, and acetalation and subsequent O-acetylation of glycosides and thioglycosides in one-pot using stoichiometric reagents.
A series of 5'-O-glycosyl-uridine and thymidine derivatives have been prepared as potential mimics of sugar nucleotides and nucleotide-diphosphates. These compounds proved not to be inhibitors of bovine beta-1,4-galactosyltransferase although some showed moderate inhibition of Salmonella dTDP-alpha-D-glucose 4,6-dehydratase (RmlB).
Pectic polysaccharide RG-II, a key component of plant primary cell walls, is known to exist as a dimer formed by means of borate diester cross-links between apiosyl residues of one of its constituent side-chain oligosaccharides. Described herein is the strategy for the synthesis of the branched tetrasaccharide alpha-d-GalA-(1-->2)-[beta-D-GalA-(1-->3)]-[alpha-L-Fuc-(1-->4)]-alpha-L-Rha-OMe, an RG-II fragment that is linked to the apiosyl residue that is thought to be responsible for the borate complexation in RG-II dimer. Iterative glycosylation of the rhamnoside acceptors derived from the key 2,3-orthoacetate of methyl 4-O-methoxybenzyl-alpha-d-rhamnopyranoside afforded the protected tetrasaccharide. The target dicarboxylic acid saccharide was subsequently prepared by removal of protecting groups followed by TEMPO-mediated oxidation of galactopyranosyl residues to galactopyranosyluronic acids.
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Solvent-free per-O-acetylation of sugars with stoichiometric acetic anhydride and catalytic iodine proceeds in high yield (90-99%) to give exclusively pyranose products as anomeric mixtures. Without workup, subsequent anomeric substitution employing iodine in the presence of hexamethyldisilane (i.e., TMS-I generated in situ) gives the corresponding glycosyl iodides in 75-95% isolated yield. Alternatively, and without workup, further treatment with dimethyl disulfide or thiol (ethanethiol or thiocresol) gives anomerically pure thioglycosides in more than 75% overall yield.
Enzymatic and chemo-enzymatic approaches provide straightforward access to uridine diphospho sugars irrespective of the relative and absolute configuration of the sugar, its ring size and substitution pattern.
The branched tetrasaccharide, O-beta-d-glucopyranosyl-(1-->2)-O-[beta-d-xylopyranosyl-(1-->3)]-O-beta-d-glucopyranosyl-(1-->4)-d-galactose (lycotetraose) is a key constituent of many biologically interesting natural products. Described herein is a convenient enzymatic preparation of lycotetraose from the readily available Solanum glycoalkaloid alpha-tomatine. The preparation makes use of the recombinant endo-glycosidase, tomatinase, from the plant pathogen Fusarium oxysporum f. sp. lycopersici.
[reaction: see text] The preparation of a range of alkyl and aryl chiral vinyl aziridines was achieved in high yield and stereoselectivity, and with excellent diastereoselectivity, by reaction of tert-butylsulfinylimines with the ylide derived from S-allyl tetrahydrothiophenium bromide.
Vancomycin, the last line of defense antibiotic, depends upon the attachment of the carbohydrate vancosamine to an aglycone skeleton for antibacterial activity. Vancomycin is a naturally occurring secondary metabolite that can be produced by bacterial fermentation. To combat emerging resistance, it has been proposed to genetically engineer bacteria to produce analogues of vancomycin. This requires a detailed understanding of the biochemical steps in the synthesis of vancomycin. Here we report the 1.4 A structure and biochemical characterization of EvaD, an RmlC-like protein that is required for the C-5' epimerization during synthesis of dTDP-epivancosamine. EvaD, although clearly belonging to the RmlC class of enzymes, displays very low activity in the archetypal RmlC reaction (double epimerization of dTDP-6-deoxy-4-keto-D-glucose at C-3' and C-5'). The high resolution structure of EvaD compared with the structures of authentic RmlC enzymes indicates that a subtle change in the enzyme active site repositions a key catalytic Tyr residue. A mutant designed to re-establish the normal position of the Tyr increases the RmlC-like activity of EvaD.
Chemical syntheses of two disaccharides, benzyl beta-D-glucopyranosyl-(1-->2)-alpha-L-arabinopyranoside (1) and benzyl beta-D-glucopyranosyl-(1-->4)-alpha-L-arabinopyranoside (2), and a trisaccharide, benzyl beta-D-glucopyranosyl-(1-->2)-3-O-acetyl-4-O-(beta-D-glucopyranosyl)-alpha-L-arabinopyranoside (3), related to oat root triterpenoid saponin Avenacin A-1 are reported.
Methanol dried extensively over molecular sieves, or methanol in combination with powdered molecular sieves, serves as a good acceptor for acyl transfer reactions. Several O-acetylated and O-benzoylated sugar derivatives were efficiently de-O-acylated using this approach. In the case of per-O-acetylated N-acetylglucosamine, selective anomeric deprotection could be effected in high yield.
Beta-rhamnosylation of methyl 2-C-hydroxymethyl-2,3-O-isopropylidene-beta-D-erythrofuranoside and methyl 2,3-O-isopropylidene-beta-D-ribofuranoside was achieved using 4-O-acetyl-2,3-O-carbonyl-alpha-L-rhamnopyranosyl bromide and Ag2O as a promoter. Deprotected disaccharides beta-L-Rhap-(1-->3')-beta-D-Apif-OMe and beta-L-Rhap-(1-->3')-beta-D-Ribf-OMe were compared to their alpha-rhamnosyl isomers which were prepared using conventional Helferich glycosylation.
A simple one-pot method is reported for making partially protected glycosyl acceptors from O-methyl or S-alkyl/aryl glycosides of D-glucose, D-galactose, D-arabinose, L-rhamnose, L-fucose and lactose via orthoester formation, benzylation and selective hydrolysis.
Recently, carbohydrates have come to the fore because of their central role in many biological processes. One area of current interest concerns the enzymatic modification of sugar nucleotides, in relation to both secondary metabolite glycosylation and the formation of complex cell surface-associated glycoconjugates. Bacteria, in particular, have proven to be a rich field in which to study these transformations, because they are often unique to specific classes of organisms. This has led to the realization that such microbial biosynthetic pathways might be exploited in the generation of novel antibiotics, or indeed serve as targets for such compounds. This work illustrates the interplay between protein structure determination, chemistry, and molecular biology in providing insight into the mechanism of such biochemical transformations.
Highly selective reaction of methyl tetra-O-pivaloyl-beta-D-glucopyranuronate 2 with iodotrimethylsilane or (Me3Si)2 and I2 affords, in excellent yield, the 'disarmed' glycosyl iodide 1 which has good stability at 20 degrees C and excellent stability at 0 degrees C; the X-ray crystal structure of 1 is described, along with a comparison of its utility as a glycosyl donor to that of the corresponding bromide.
Mercuric bromide-promoted glycosylation of Fmoc-Ser-OBn and Fmoc-Thr-OBn with 2-acetamido-2-deoxy-3,4,6-tri-O-acetyl-alpha-D-glucopyranosyl chloride in refluxing 1,2-dichloroethane gave the corresponding beta-glycosides in good yields (64 and 62%, respectively). Direct coupling of the commercially available Fmoc-Ser-OH and Fmoc-Thr-OH carboxylic acids under similar conditions gave the corresponding beta-glycosides, possessing free carboxyl groups, in moderate yields (50 and 40%, respectively).