Pharmacological Activities of Sulfated Carbohydrate Polymers

Abstract

Among the large group of naturally occuring polysaccharide-sulfates, the glycosaminoglycans (GAG) such as heparin, heparansulfate, chondroitinsulfate, dermatansulfate and keratansulfate are biologically important polymers. The best known of these compounds is heparin, where the position of the sulfate groups is essential for any anticoagulant effect. In awareness of various contaminants in natural products of animal origin, there is increasing fear that many products from bovine or lifestock origin many be contaminated. This has stimulated the development of synthetic heparin-analogs (heparinoids) such as the heparin pentasaccharide and others. Another source for sulfated polysaccharides are the sulfated biopolymers of marine origin such as the carrageenans, fucoidans, fucans and other algal cell wall polysaccharides, which in part have been examined for anticoagulant and antithrombotic effects. Suflated polysaccharides from bacterial origin are of special drug innovation intererst, since large amounts of the starting polymer can be obtained by biotechnological methods. Another group of sulfated polysaccharides consists of the semisynthetic polysaccharide sulfates such as dextransulfate, pentosan-polysulfate, chitosansulfate and finally β3-1.3 glucansulfates.

The group of linear or slightly branched glucans of bacterial origin was chosen for studies about the mechanisms of polysaccharide-sulfate protein interactions in the series of physiological events in the coagulation cascade. With sulfated β-1.3 glucans, differing in DS, sulfate position and chain length, it was tried to establish an ideal anticoagulant polymer which could serve as valuable leadstructure for the future development of an optimal carbohydrate based antithrombotic drug.

Besides antithrombotic and antiviral effects, sulfated polysaccharides are known to inhibit the complex process of angiogenesis, i.e. the growth and development of new blood vessels, which occurs in many tissues and is a prerequisite of tumor progression. Tumor growth and metastasis is angiogenesis dependent when an increasing number of new capillaries converge upon a tumor. Inhibition of angiogenesis, without cytotoxic side effects, is one of the new approaches of tumor treatment. The basic fibroblast growth factor (bFGF) has been shown to be one of the most potent angiogenic molecules. Since it is known that heparin and heparin-like structures have a high affinity towards bFGF and thereby act as a regulator of its function, the search for other heparin-like polymers was initiated. Heparin itself has the disadvantage of uncontrolled bleeding risk when applied in a systemic treatment.

A series of other sulfated polysaccharides differing in their basic structures (primary structure, type of glycosidic linkage, degree of sulfation, chain length) was examined in the CAM-assay.

Genuine carrageenans and modified carrageenans were tested for their ability to inhibit the formation of new blood capillaries with good success, however, they had considerable side effects. Better results were obtained with a series of modified galactans. It could be shown that β-1.4-galactansulfates of relatively low DP with a distinct DS have very interesting antiangiogenic activity. These non-cytotoxic galactan structures are further developed as angiogenesis inhibitor lead-structures.