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

A Synthetic Antithrombin III Binding Pentasaccharide Is Now a Drug! What Comes Next?

“…To this end we prepared a series of compounds, such as 27 and 28 , in which various TBDs and an ABD are separated by a neutral fully methylated domain (Figure 30). 28, 37 We found that the size of the thrombin‐binding site can even be as small as a mono‐ or disaccharide fragment, and again we confirmed that the interaction with thrombin also depends on charge density. The experience gained during the synthesis of the conjugates was very useful in the design of the TBD.…”

“…Consequently, we anticipated that a rigid linker with the appropriate configuration would enhance the formation of the ternary complex and thus lead to increased antithrombin activity (Figure 23). As a neutral rigid spacer we used an octasaccharide made up of glucopyranose units with alternating α‐ and β‐1,4‐glycoside linkages,28 which closely resembles the backbone structure of heparin. This rigid conjugate is a hexadecasaccharide ( 15 in Figure 23) and has superior antithrombin activity (1200 U mg −1 ) to the conjugate 14 (40 U mg −1 ) and to heparin (160 U mg −1 ).…”

“…This rigid conjugate is a hexadecasaccharide ( 15 in Figure 23) and has superior antithrombin activity (1200 U mg −1 ) to the conjugate 14 (40 U mg −1 ) and to heparin (160 U mg −1 ). The hexadecasaccharide belongs to a family of synthetic long heparin‐like fragments that show superb antithrombin activity (see Section 5) 28…”

New antithrombin‐based anticoagulants

“…Comparison of a flexible polyethylene glycol type spacer with a rigid polyglucose type spacer suggested that the rigid spacer gave higher anti-factor IIa activity. 188 More importantly, these anticoagulants elicited much lower platelet factor 4 binding activity, thus suggesting that these heparin mimics are likely to reduce heparin-induced thrombocytopenic adverse effects.…”

Kohlenhydratmimetika: ein neuer Lösungsansatz für das Problem der kohlenhydratvermittelten biologischen Erkennung

“…Weiterhin wurde postuliert, daû eine Verringerung der Ladungsdichte in der Region zwischen der AT-III-Bindungsstelle und der Thrombin-Bindungsstelle die nichtspezifischen Bindungseffekte herabsetzen könnte. [100] Dreef-Tromp und Mitarbeiter [101] verbanden eine Thrombin-Bindungsstelle und eine AT-III-Bindungsregion mit ungeladenen, flexibler Ketten. Sie verknüpften eine Thrombin-Bindungsregion (persulfatierte Maltotriose) mit dem Pentasaccharid aus Abbildung 26 a über einen flexiblen Polyethylenlinker (Abbildung 26 c) oder über einen ungeladenen Polysaccharidlinker.…”