Pieter Westerduin

Rational design of synthetic heparin analogues with tailor-made coagulation factor inhibitory activity.

Computer modelling of the antithrombin III–heparin–thrombin complex inspired the synthesis of novel glycoconjugates, whose factor Xa and thrombin inhibitory activites can be adjusted in a rational way, leading to anticoagulants with unprecedented characteristics.

Polymer-supported solution synthesis of heparan sulphate-like oligomers

Abstract The polyethylene glycol (PEG-polymer)-supported solution synthesis of heparan sulphate-like oligomers, which differ in length (up till 12-mers) and sulphation pattern, is described.1

Synthesis of a pentasaccharide and a heptasaccharide corresponding to an ovarian glycoprotein; studies towards glycosylations

Abstract The syntheses of pentasaccharide I and heptasaccharide II , which correspond to an ovarian O-glycoprotein, are presented. The protected pentasaccharide 1 was prepared by condensing a trisaccharide donor 18c with a disaccharide acceptor ( 8b , while condensation of the same trisaccharide donor ( 18c ) with a tetrasaccharide acceptor ( 25b ) provided the protected heptasaccharide 2 . Special attention was paid to the deblocking of the protected derivatives 1 and 2 to give I and II , respectively. The β-bonds in 8b and 25b were prepared by using glycosyl donors with non -participating groups at C-2, which were earlier applied for the synthesis of α-glycosides. For the synthesis of the trisaccharide donor ( 18c ), condensations of several activated Galα(1->3)Gal disaccharides with protected GlcNAc residues were compared. It was found that the α/β ratio and the yield of this glycosylation are influenced by the leaving group at the anomeric centre, the character of the participating acyl group and, in particular, by the unfavourable steric interaction between donor and acceptor. In order to reduce this steric interaction between donor and acceptor, the conformation of the GlcNAc acceptor was changed to the 1,6-anhydro derivative 16 , which afforded in the glycosylation with glycosyl bromide 13c a high yield of the desired trisaccharide 17 .

Total synthesis of new 1,5-bissubstituted myo-inositol derivatives. Synthesis of D-myo-inositol 1,5-bisphosphate, 3,5-bisphosphate and of rac. 1,5-Bissulphated and 1,5-bissulphamoylated isosteric analogues

Abstract Convenient synthesis of D-myo-inositol 1,5-bisphosphate, 3,5-bisphosphate and isosteric rac. 1,5-bissulphate and 1,5-bissulphonamide was accomplished from key intermediate 2,3,4,6-tetra-O-benzyl-myo-inositol.

Synthesis of methyl 3-[3-(2-O-α-L-rhamnopyranosyl-α-L-rhamnopyranosyloxy)decanoyloxy]decanoate, a rhamnolipid from Pseudomonas aeruginosa

Abstract Condensation of (3 R )-3-levulinoyloxydecanoic acid ( 16 ) with methyl (3 R )-3-hydroxydecanoate ( 13 ) afforded, after selective delevulinoylation, methyl (3 R )-3-[(3 R )-3-hydroxydecanolyloxy]decanoate ( 18 ). Boron trifluoride etherate-promoted coupling of 3,4-di- O -benzyl-2- O -chloroacetyl-α- l -rhamnosyl fluoride ( 11 ) with 18 yielded exclusively an α-glycoside 19 , which, after removal of the chloroacetyl group, coupling with 11 , and removal of the protecting groups, afforded the title rhamnolipid 1 .

Glycosaminoglycans: Synthetic fragments and their interaction with serine protease inhibitors

Glycosaminoglycans such as e.g. heparin, heparan sulphate and dermatan sulphate display a broad variety of biological activities. Unique, Well-defined domains in some glycosaminoglycans have been characterized that are responsible for the biological activity. For instance, a unique pentasaccharide domain in heparin could be identified which binds and activates the serine protease inhibitor (serpin) anti-thrombin I11 (AT 111). The structure-activity relationships of various synthetic counter-parts of the heparin pentasaccharide fragment reveal the highly specific nature of the pentasaccharide mediated activation of AT 111. With the aid of molecular modelling and the availability of crystal structures of serpins and their target proteases, the activation process of AT I11 by heparin becomes understood at the molecular level. Some attention will also be paid to well-defined domains in heparan sulphate and dermatan sulphate.

Synthesis of analogues of myo-inositol 1,4,5-trisphosphate that contain sulfonamide, sulfate, methylphosphonate, and carboxymethyl groups

The syntheses are described of four isosteric racemic myo-inositol 1,4,5-trisphosphate (1) analogues with the phosphate groups replaced by sulfonamide (2), sulfate (3), methylphosphonate (4), and carboxymethyl (5). None of these compounds had any affinity for the IP3 receptor or induced platelet aggregation.

Synthesis of 1,4,5-trissulphated and 1,4,5-trissulphamoylated myo-inositols: Isosteric myo-inositol 1,4,5-trisphosphate analogues

Abstract Synthesis of the myo-inositol 1,4,5-trisphosphate isosteric analogues (rac.) 1,4,5-trissulphate and (rac.) 1,4,5-trissulphonamido was accomplished from 1,2,4-tri-O-benzyl myo-inositol.

Synthesis of two purple-membrane glycolipids and the glycolipid sulfate O-(β-d-glucopyranosyl 3-sulfate)-(1→6)-O-α-d-mannopyranosyl-(1→2)-O-α-d-glucopyranosyl-(1→1)-2, 3-di-O-phytanyl-sn-glycerol

The two purple-membrane glycolipids O-β-d-glucopyranosyl- and O-β-d-galactopyranosyl-(1→6)-O-α-d-mannopyranosyl-(1→2)-O-α-d-glucopyranosyl-(1→1)-2, 3-di-O-phytanyl-sn-glycerol were prepared by coupling O-(2,3,4-tri-O-acetyl-α-d-mannopyranosyl)-(1→2)-O-(3,4,6-tri-O-acetyl-α-d-glucopyranosyl)-(1→1)-2, 3-di-O-phytanyl-sn-glycerol (9) with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide or 2,3,4,6-tetra-O-acetyl-α-d-mannopyranosyl bromide, respectively, followed by deacetylation. The glycolipid sulfate O-(β-d-glucopyranosyl 3-sulfate)-(1→6)-O-α-d-mannopyranosyl-(1→2)-O-α-d-glucopyranosyl-(1→1)-2,3-di-O-phytanyl-sn-glycerol was prepared by coupling of 9 with 2,4,6-tri-O-acetyl-3-O-trichloroethyloxycarbonyl-α-d-glucopyranosyl bromide in the presence of Hg(CN)2/HgBr2 followed by selective removal of the 3‴-trichloroethyloxycarbonyl group, sulfation of HO-3‴, and deacetylation. The suitably protected key-intermediate 9 could be prepared by two distinct approaches.

Synthesis of racemic myo-inositol 1,4,5-trismethylphosphonate, myo-inositol 4,5-bismethylphosphonate and myo-inositol 5-methylphosphonate via a phosphinate approach

Abstract Synthesis of the (rac.) myo-inositol phosphate isosteric analogues 1,4,5-trismethylphosphonate, 4,5-bismethylphosphonate, and 5-methylphosphonate was accomplished using a phosphinate approach.