Jan E. M. Basten

Design and synthesis of a novel synthetic NAPAP-penta-saccharide conjugate displaying a dual antithrombotic action

The synthesis of a novel antithrombotic consisting of a heparin pentasaccharide conjugated to the active site inhibitor N-(2-naphtalenesulfonyl)-glycyl-(D)-4-aminophenyl-alanyl-piperidin e (NAPAP) (i.e. compound I) is reported. This conjugate shows a unique pharmacological profile both in vitro and in vivo having direct anti-thrombin and ATIII-mediated anti-Xa activity. Furthermore, conjugate I has a prolonged in vivo half-life compared to NAPAP (1.5 h vs 9 min.).

Biologically active heparin-like fragments with a “non-glycosamino”glycan structure. Part 3 : o-alkylated-o-sulphated pentasaccharides.

Abstract The synthesis of analogues of biologically active heparin pentasaccharide fragments is reported. Replacement of N-sulphate by O-sulphate esters and introduction of various O-alkyl ethers resulted in biologically active “non-glycosamino“glycans. The biological activity can be further modulated by changing the nature and the position of the alkyl chains introduced.

Biologically active heparin-like fragments with a “non-glycosamino”glycan structure. Part 1: a pentasaccharide containing a 3-O-methyl iduronic acid unit.

Abstract We describe a new approach towards biologically active analogues of glycosaminoglycan fragments where N-sulphates are replaced by O-sulphates and free hydroxyls are substituted by alkyl ethers. Here we demonstrate that introduction of a methyl group at the 3 position of L-iduronic acid residue neither affects the AT III mediated anti-factor Xa activity nor alters the conformational properties of a unique haparin pentasaccharide sequence.

Biological properties of synthetic glycoconjugate mimics of heparin comprising different molecular spacers

The in vitro antithrombotic activity of synthetic glycoconjugates I and II, comprising a flexible polyethylene glycol type and a rigid polyglucose type spacer, respectively, are compared to heparin.

Biologically active heparin-like fragments with a “non-glycosamino”glycan structure. Part 2 : a tetra-o-methylated pentasaccharide with high affinity for antithrombin III.

Abstract To simplify the preparation of biologically active oligosaccharide analogues of glycosaminoglycan fragments we describe an approach where N-sulphates are replaced by O-sulphates and free hydroxyls are substituted by methyl groups. In this communication we report on the synthesis of a pentasaccharide in which hydroxyl groups of the non-reducing end disaccharide sub-region are methylated. The biological properties of this chemically modified analogue are fully preserved.

Synthesis of heparin-like antithrombotics having perphosphorylated thrombin binding domains

The synthesis of three heparin analogues (i.e. compounds VI-VIII) having perphosphorylated thrombin binding domains (TBDs) is reported. These compounds were tested in vitro for their antithrombin III (ATIII)-mediated anti-Xa and antithrombin activities. Conjugates VI and VIII show a remarkable increase in antithrombin activity compared to the structurally related conjugates with persulfated TBDs (i.e. compounds IV and V), whereas compound VII displays a diminished activity.

In vitro evaluation of synthetic heparin-like conjugates comprising different thrombin binding domains

The syntheses of several heparin-like glycoconjugates (i.e., 16a-f) containing identical AT III binding domains (ABD) and spacers but different thrombin binding domains (TBDs) are described. Biological activities of conjugates 16a-f indicate that the thrombin inhibitory activity is mainly determined by the charge density of the TBD moiety.

Synthesis of a dermatan sulphate-like hexasaccharide with a “non-glycosamino” glycan structure

Abstract The synthesis of a “non-glycosamino” glycan counterpart (i.e. compound II ) of a naturally occuring dermatan sulphate hexasaccharide that binds with high affinity to heparin cofactor II is described.

The action of serpins and heparin as leads in drug discovery

Abstract The natural product heparin is an important lead in research on antithrombotics. By molecular modification of a unique heparin fragment new derivatives were discovered. One of them, the synthetic counterpart of the antithrombin III binding pentasaccharide 1 , is now being tested clinically. Recently, the structure elucidation of a number of blood coagulation proteins and serpins initiated a new breakthrough in the anticoagulant research. Molecular modelling of the crucial antithrombin III — heparin — thrombin complex inspired the design and synthesis of a novel class of anticoagulants. Their anticoagulant properties can be adjusted in a rational way leading to compounds with unprecedented characteristics.