Torbjörn Frejd

Boron trifluoride etherate as an effective reagent for the stereoselective one-pot conversion of acetylated 2-trimethylsilylethyl glycosides into sugar 1,2-trans-acetates

Summary Treatment of 2-trimethylsilylethyl glycosides with boron trifluoride etherate in the presence of acetic anhydride gave the corresponding sugar acetate in >90% isolated yield and with a 1,2- trans : cis ratio of >20:1. The sugar with a free anomeric hydroxyl group was obtained when acetic anhydride was omitted.

An enantiospecific synthesis of a taxol A-ring building unit

Abstract The optically active Taxol A-ring segment 2 was synthesized from L-arabinose via ring closure of epoxy-allylsilane 3 with BF 3 .OEt 2 .

Synthesis of di-, tri-, and tetra-saccharides corresponding to receptor structures recognised by Streptococcus pneumoniae

Abstract Syntheses are described for methyl 2-acetamido-2-deoxy-4- O -β- d -galactopyranosyl-α- d -glucopyranoside, methyl 2-acetamido-2-deoxy-4- O -β- d -galactopyranosyl-β- d -glucopyranoside, methyl 3- O -(2-acetamido-2-deoxy-β- d -glucopyranosyl-β- d -galactopyranoside, methyl 3- O -(2-acetamido-2-deoxy-4- O -β- d -galactopyranosyl-β- d -glucopyranosyl)-β- d -galactopyranoside, and methyl 4- O -[3- O -(2-acetamido-2-deoxy-4- O -β- d -galactopyranosyl-β- d -glucopyranosyl)-β- d -galactopyranosyl]- β- d -glucopyranoside.

Synthesis of spacer-arm, lipid, and ethyl glycosides of the trisaccharide portion [α-D-Gal-(1→4)-β-D-Gal-(1→4)-β-D-Glc] of the blood-group Pk antigen: preparation of neoglycoproteins

Abstract The title compounds were prepared via the acetylated 2-bromoethyl glycoside 11 of α- d -Gal-(1→4)-β- d -Gal-(1→4)-β- d -Glc by displacement of bromide ion with methyl 3-mercaptopropionate, octadecanethiol, and hydrogen, respectively. Silver triflate-promoted glycosylation of 2-bromoethyl 2,3,6-tri-O-benzyl-β- d -glucopyranoside with 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α- d -galactopyranosyl)-α- d -galactopyranosyl bromide gave 11. A tetradeuterated analogue of 11 was prepared by essentially the same route. The spacer-arm glycoside formed from methyl 3-mercaptopropionate was coupled to bovine serum albumin and keyhole limpet haemocyanin.

Synthetic receptor analogues: preparation of the 3-O-methyl, 3-C-methyl, and 3-deoxy derivatives of methyl 4-O-α-D-galactopyranosyl-β-D-galactopyranoside (methyl β-D-galabioside)

Abstract Methyl β- d -galactopyranoside was transformed into methyl 2- O -benzyl- ( 5 , 24%) and 2- O -benzyloxymethyl-4,6- O -benzylidene-β- d -galactopyranoside ( 8 , 60%) in two and four steps respectively. Compounds 5 and 8 were then transformed into the corresponding 3- O -methyl, 3- C -methyl, and 3-deoxy derivatives variously by O -methylation, Wittig olefination/stereospecific hydrogenation, and xanthate reduction. Regioselective reductive opening of the 4,6- O -benzylidene rings gave galactoside derivatives with HO-4 unsubstituted. Bromide-ion catalysed α- d -galactosidation and hydrogenolysis of the benzyl protecting-groups then gave the desired β- d -galabioside analogues.

Synthetic receptor analogues: the conformation of methyl 4-O-α-d-galactopyranosyl-β-d-galactopyranoside (methyl β-d-galabioside) and related derivatives, determined by N.M.R. and computational methods

Abstract The conformations of galabiose and its methyl and ethyl β-glycosides as well as the 3-deoxy, 3- O -methyl, 3-deoxy-3- C -methyl, 3-deoxy-3- C -ethyl, and 6-deoxy analogues were investigated by n.m.r. ( 1 H, 13 C, n.O.e.) and computational (HSEA) methods. A good correlation was found between the computational data and the n.m.r. data for aqueous solutions. The conformations in aqueous solution were similar, whereas crystalline galabiose or methyl β- d -galabioside in solution in methyl sulfoxide adopted different conformations that showed intramolecular hydrogen bonds (O-5′ ··· O-3 and O-2′ ··· O-6, respectively).

Synthesis of optically active cyclohexenol derivatives via enzyme catalyzed ester hydrolysis of 4-acetoxy-3-methyl-2-cyclohexenone

Abstract The optically active cyclohexenol derivatives 9a–9d, and 10a–10c are synthesized from (−)-6, which is obtained by enzymatic ester hydrolysis of racemic 8. Attempts towards the synthesis of the taxane skeleton are described.

Synthetic receptor analogues: preparation and calculated conformations of the 2-deoxy, 6-O-methyl, 6-deoxy, and 6-deoxy-6-fluoro derivatives of methyl 4-O-α-d-galactopyranosyl-β-d-galactopyranoside (methyl β-d-galabioside)☆

Abstract The 2-deoxy (7), 6-O-methyl (15), 6-deoxy (22), and 6-deoxy-6-fluoro (31) derivatives of methyl β- d -galabioside (1) have been synthesised. Thus, 7 was prepared by xanthate reduction using tributyltin hydride, whereas 22 was obtained by catalytic hydrogenation of a 6-deoxy-6-iodogalabioside. Regioselective mono-fluorination of methyl 2,3-di-O-benzoyl-β- d -galactopyranoside with Et2NSF3 and subsequent α- d -galactosylation provided 31. Molecular mechanics calculations yielded similar conformations for 1, 7, 15, 22, and 31 with differes in φH and ψH of 5°. No indications of intramolecular hydrogen bonds, as displayed by 1 in the crystal, were found for 7, 15, 22, or 31.

Flavonoids as inhibitors of human carbonyl reductase 1

Human carbonyl reductase 1 (CBR1), that is one of the enzymes responsible for the reduced efficiency of treatments by the antineoplastic agents anthracyclines, was functionally expressed in Saccharomyces cerevisiae. CBR1 was purified and kinetically characterised using daunorubicin as substrate. CBR1-catalysed reduction of daunorubicin followed an apparent Michaelis-Menten kinetics with K(M)=85.2+/-26.7microM and V(max)=3490+/-220micromol/(mingprotein). The type of inhibition for the flavonoid compound rutin was determined by studying initial reaction rates in the presence of rutin. The inhibition kinetics was found to follow an apparent mixed inhibition with K(ic)=1.8+/-1.2microM and K(iu)=2.8+/-1.6microM. IC50-values were also determined for a set of flavonoids in order to identify essential structure for inhibition activity. Computational docking experiments of the four best inhibitors to the catalytic site of CBR1 showed that the flavonoid skeleton structure was the binding part of the molecule. The presence of a sugar moiety in 1 and 2, or a sugar mimicking part in 9, directed the orientation of the flavonoid so that the sugars were pointing outwards, giving rise to a stabilising effect to the binding. Finally, additional binding epitopes that interacted with various parts of the flavonoid ligand were identified and could potentially be targeted for further improvement of inhibition activity. These included; hydrogen-binding sites surrounding Ser139 and Cys226, Met234 and Tyr193 or Trp229; aromatic-aromatic interaction with Tyr193, Trp229 or NADPH; van der Waals interactions with Ile140.

Monovalent Interactions of Galectin-1

Galectin-1, a β-galactoside binding lectin involved in immunoregulation and cancer, binds natural and many synthetic multivalent glycoconjugates with an apparent glycoside cluster effect, that is, affinity above and beyond what would be expected from the concentration of the determinant sugar. Here we have analyzed the mechanism of such cluster effects in solution at physiological concentration using a fluorescence anisotropy assay with a novel fluorescent high-affinity galectin-1 binding probe. The interaction of native dimeric and monomeric mutants of rat and human galectin-1 with mono- and divalent small molecules, fetuin, asialofetuin, and human serum glycoproteins was analyzed. Surprisingly, high-affinity binding did not depend much on the dimeric state of galectin-1 and thus is due mainly to monomeric interactions of a single carbohydrate recognition domain. The mechanism for this is unknown, but one possibility includes additional interactions that high-affinity ligands make with an extended binding site on the carbohydrate recognition domain. It follows that such weak additional interactions must be important for the biological function of galectin-1 and also for the design of galectin-1 inhibitors.