Semi-Synthetic Strategies towards (Fucosylated) Chondroitin Sulfate Polysaccharides with a High Control of Their Structural Modifications

S5.3 Oligosaccharide synthesis II
Location (hall): 
Start/end time: 
Tuesday, July 2, 2019 - 15:40 to 15:45

Giulia Vessella1, Alfonso Iadonisi1, Chiara Schiraldi2, Emiliano Bedini1

1Department of Chemical Sciences, University of Naples Federico II, Napoli, Italy, 2Department of Experimental Medicine, University of Campania L. Vanvitelli, Napoli, Italy

Chondroitin sulfate (CS) and fucosylated chondroitin sulfate (fCS) are natural heteropolysaccharides belonging to the glycosaminoglycan (GAG) family. From a structural point of view, both of them are composed of a saccharide backbone consisting of a -4)-β-GlcA-(1-3)-β-GalNAc-(1- disaccharide repeating unit. CS is widely distributed in mammals and invertebrates as well as in some bacteria and, depending on the natural source, it displays different sulfation patterns, so several disaccharide subunits could be described. [1] Instead, fCS, found up to now exclusively in sea cucumbers, usually shows variously sulfated L-fucose (Fuc) monosaccharides or, much more rarely, oligosaccharide branches linked through an α-configured glycosidic bond at C-3 of GlcA units or, in very few cases, at C-6 of GalNAc. [2] 

Both of these polysaccharides have attracted much attention for their biological properties and biomedical applications. CS, commonly obtained by extraction from bovine, porcine or shark cartilage, is currently used in treatment of osteoarthritis, but further potential employments have been proposed depending on different sulfation patterns. [3] fCS presents several biological activities too; its anti-coagulant and anti-thrombotic properties are particularly remarkable since they make fCS a potential alternative to heparin as orally deliverable anti-coagulant drug. [4] 

However, the pharmacological applications of these natural-sourced polysaccharides are limited by several factors, including the low abundance of raw material and the laborious downstream purification, the ever-stricter regulations for animal-derived drugs and the natural high variability of the sulfation patterns. The last aspect requires a strict control of the sulfation level in these products, since some sulfation patterns can be even dangerous for human health.

For these reasons, many efforts have been devoted to the development of synthetic or semi-synthetic approaches for the obtainment of CS and fCS oligo- or polysaccharide derivatives. [5] In particular, recent semi-synthetic methods have gained a library of (f)CS polysaccharides, in which, though, the sulfation or fucosylation patterns were only partially controlled. [6]   

These results have encouraged us to look for novel semi-synthetic strategies in order to increase the site-selectivity of sulfation and  fucosylation. Starting from a microbial-sourced chondroitin polysaccharide, finely-tuned sequences of protection-deprotection steps have been designed based on the employment of bulky protecting groups, selective deprotection reactions and reaction conditions already tested on mono- or oligosaccharides.

The obtainment of homogeneous semi-synthetic (f)CS polysaccharides will allow wider and more accurate structure-activity relationship studies with respect to those reported in literature to date.

  1. Chondroitin Sulfate: Structure, Use and Health Implications; Pomin, V. H., Ed.; Nova Science Publishers, Inc.: Hauppauge, NY, 2013. 
  2. Myron, P.; Siddiquee, S.; Al Azad, S. Carbohydr. Polym. 2014, 112, 173-178. 
  3. Yamada, S.; Sugahara, K. Curr. Drug Discovery Technol. 2008, 5, 289-301.
  4. Pomin, V.H. Mar. Drugs 2014, 12, 232-254.
  5. a) Vibert, A.; Lopin-Bon, C.; Jacquinet, J.C. Chem. Eur. J. 2009, 15, 9561-9578; b) Tamura, J.I.; Tanaka, H.; Nakamura, A.; Takeda, N. Tetrahedron Lett. 2013, 54 , 3940–3943; c) Zhang, X.; Liu, H.; Lin, L.; Yao, W.; Zhao, J.; Wu, M.; Li, Z. Angew. Chem. Int. Ed. 2018, 57, 12880-12885.
  6. a) Bedini, E.; De Castro, C.; De Rosa, M.; Di Nola, A.; Iadonisi, A.; Restaino, O.F.; Schiraldi, C.; Parrilli, M. Ange. Chem. Int. Ed. 2011, 50, 6160 –6163; b) Bedini, E.; De Castro, C.; De Rosa, M.; Di Nola, A.; Restaino, O.F.; Schiraldi, C.; Parrilli, M. Chem. Eur. J. 2012, 18, 2123 – 2130; c) Laezza, A.; Iadonisi, A.; Pirozzi, A. V. A.; Diana, P.; De Rosa, M.; Schiraldi, C.; Parrilli, M.; Bedini, E. Chem. Eur. J. 2016, 22, 18215-18226.