Abstract
Fucosylated chondroitin sulfate (fCS) is a glycosaminoglycan found up to now exclusively in the body wall of sea cucumbers. It shows several interesting activities, with the anticoagulant and antithrombotic as the most attractive ones. Its different mechanism of action on the blood coagulation cascade with respect to heparin and the retention of its activity by oral administration make fCS a very promising anticoagulant drug candidate for heparin replacement. Nonetheless, its typically heterogeneous structure, the detection of some adverse effects and the preference for new drugs not sourced from animal tissues, explain how mandatory is to open an access to safer and less heterogeneous non-natural fCS species. Here we contribute to this aim by investigating a suitable chemical strategy to obtain a regioisomer of the natural fCS polysaccharide, with sulfated l-fucosyl branches placed at position O-6 of N-acetyl-d-galactosamine (GalNAc) units instead of O-3 of d-glucuronic acid (GlcA) ones, as in natural fCSs. This strategy is based on the structural modification of a microbial sourced chondroitin polysaccharide by regioselective insertion of fucosyl branches and sulfate groups on its polymeric structure. A preliminary in vitro evaluation of the anticoagulant activity of three of such semi-synthetic fCS analogues is also reported.
Highlights
Proteoglycans are one of the major, most ubiquitously distributed and most important components of the extracellular matrix and cell surfaces, playing several essential roles in a variety of biological events
A differentiation between GalNAc and glucuronic acid (GlcA) hydroxyls in Escherichia coli O5:K4:H4 sourced chondroitin could be done by protection of the diol on GalNAc units with a benzylidene ring [30], followed by acetylation of GlcA diol
[32], [32], we focused our attention on thoseonshowing the following severalvariants variantsthat that have been reported we focused our attention those showing the features, necessary for an application on chondroitin polysaccharide derivative
Summary
Proteoglycans are one of the major, most ubiquitously distributed and most important components of the extracellular matrix and cell surfaces, playing several essential roles in a variety of biological events They are very complex biomacromolecules, composed of a protein core on which are anchored from one to one hundred of polysaccharide chains, termed glycosaminoglycans (GAGs). Drugs 2019, 17, 655 inistration ofMar.fCS retains its activity, because it is digested neither during its adsorption in ointestinal tract nor by intestinal bacterial enzymes [5]. These features make fCS a been the most intensely studied in the last two decades. It attracted a constantly increasing interest for mising anticoagulant candidate heparin hyperglycemia, replacement [6]
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