Biological activity of oxidized polysaccharides

Document Type

Article

Publication Date

12-1-2006

Abstract

Among the major classes of biomolecules, carbohydrates allow almost unlimited structural variations. The molecular diversity of carbohydrates offers a valuable tool for drug discovery in the areas of biologically important oligosaccharides, glycoconjugates, and molecular scaffolds by investigating their structural and functional impact. The high density of functional groups per unit mass and the choice of stereochemical linkages at the anomeric carbon have always challenged synthetic chemists toward a multitude of approaches to this rich class of compounds. The last decade of the past century witnessed the transformation of glycoscience in a worldwide domain. The reason may be that the synthesis of a saccharide chain with biological functions does not involve nucleic acids directly. In other words, in contrast to protein synthesis by genetic information, saccharide synthesis is assisted by a number of enzymes (e.g., glycosidases and glycosyl transferases) acting on a particular position of a molecule on a particular site and at a particular time. Therefore the structure of saccharide chains depends on the environment and often it is uncertain. Many natural polysaccharides participate in a variety of in vivo biochemical reactions. However, it is quite difficult to elucidate the mechanism of their biological activity because of the complex geometry and chemical structure of natural saccharide chains, as well as due to impurities difficult to be removed. In order to understand better the relationship between the biological activity and the chemical structure of saccharide chains, chemical synthesis of polysaccharides has been attempted [1]. Several types of stereoregular polysaccharides, such as amino and deoxy polysaccharides having a linear or a branched structure were synthesized to this aim by ring-opening polymerization of anhydrosugar derivatives. There has been an intensified effort in recent years in identifying the biological functions of polysaccharides as related to potential biomedical applications. A large palette of polysaccharides derived from plants, lichens, and algae has been tested. Polysaccharides appear in many different forms in plants. They might be neutral polymers or they might be polyanionic consisting of only one type of monosaccharide, or they might have two or more, up to six different monosaccharide types. They can be linear or branched and they might be substituted with different types of organic groups, such as methyl and acetyl groups. More often than not the biologically active polysaccharides are charged, for example, when the polymers contain uronic acid units, e.g., D-galacturonic acid as in pectic polysaccharides. Other types of polysaccharides isolated from plants used in the traditional medicine were identified as having their biologically active sites in the complementary system, the case of arabinans and arabinogalactans [2]. Similar types of polysaccharides have also been shown to have dissimilar biological activities [3, 4]. Glucans have for a long time been known to have an effect on the immune system. The polymers are normally β-1,3-glucans with a certain degree of branching through C6. These glucans have been investigated especially in Asian countries, and when it was found that the glucan isolated from the edible mushroom Lentimus edodes exhibited a marked anti-tumor effect, the interest in this type of compounds arose [5-7]. In a series of works started early in 1970s Maeda et al. [8-10] reported that lentinan, a polysaccharide composed mostly of β-1,3 and β-1,6 glucosidic linkages, inhibited the growth of Sarcoma-180 transplanted subcutaneously into mice and that the anti-tumor activity was due to a host mediated reaction with participation of thymus or thymus dependent cells (T cells). The authors found that three kinds of protein components deferring from properdin increased markedly in mouse serum soon after lentinum administration. Thus, it appeared that there was a close relationship between the increase of protein components and the anti-tumor activity of polysaccharides. In addition, this fact indicated that at least in an early stage, serum factors could play an important role in the tumor regression, as well as in the cell mediated immune response [10]. A more recent publication on lentinan and related polysaccharides gives a good overview on the studies performed on these types of polymers [11]. Later on Sasaki and Nitta [12] found that the administration of curdlan with an average degree of polymerization DP = 450, at a dose of 5-50 mg/kg for 10 days, had a marked inhibitory effect on subcutaneously (SC) implanted Sarcoma-180. This glucan was also highly inhibitory active at doses of 50 and 100 mg/kg when administrated intraperitoneal (IP). The effect of this polysaccharide is thought to be host mediated because of a lack of in vitro activity. In a subsequent work Marikawa and Mizumo [13] indicated that the presence of calcium ions is essential for the anti-tumor activity of curdlan. A similar biologically active polysaccharide has been reported by Bao et al. [14]. The authors isolated a linear (1→3)-β-D-glucan from the spores of Ganoderma lucidum which affected lymphocyte proliferation and had potent stimulating effects on the immunological system. Another source of biologically active polysaccharide is Mahonia aquifolium (Pursh) Nutt. This plant from the Berberidaceae family has been used for a long time in homeotherapy as an organotropic drug for treatment of inflammatory, scaling dermatoses; it is also known as a topical anti-psoriatic drug [15]. The active principle of the mahonia tincture were thought to be the extracted alkaloids [16, 17], but some experiments led to the suggestion that there are probably other components positively influencing the immune mechanisms of human leucocytes. Kardosova et al. [18] proved that the true active component contained by Mahonia aqueous-ethanolic extract is a neutral polysaccharide with a linear (1→4)-β-D-glucan structure. The same authors [19] found that the water-extractable polysaccharide complex from the aerial parts of Rudbeckia fulgida var. sullivantii, possessed a high anti-tussive activity and Bukovsky et al. [19] reported on significant immunostimulating activity of aqueous-ethanolic extracts from the roots of the same Rudbeckia species. In viewof these findings, Kardosova and Matulova [19] provided results on isolation and structure identification of the main neutral component of the water-extractable polysaccharide mixture, a fructofuran of the inulin type. Due to its urinary tract tropism, insulin might find wider application in medicine as a drug carrier, especially of drugs to cure urogenital diseases [20]. A new type of polysaccharide was isolated from the Icelandic lichen, Thamnalia subuliformis. This polysaccharide, Thamnolan, has an unusual structure as it is basically composed of (1→3)-linked galactofuranosyl units with branched on C6, and rhamnosyl units being predominantly (1→2) linked with branches on C3 and C4, while some units are (1→3) linked. Xylose is only present as terminal units, while glucose or mannose and galactofuranosyl also are found as terminal units. Glucose and mannose are also (1→4) linked. The immunostimulating activity was tested in an in vitro phagocytosis assay and anti-complementary assay, and proved to be active in both tests [21]. Interest in the sialic acids has rapidly increased in recent years, especially since their involvement in the regulation of a great variety of biological phenomena was recognized. Based on such observation, it was recognized that sialic acids play a strong, protective role in living cells and organisms. This remarkable function of sialic acids appears to be mainly due to their peripheral position in glucoconjugates and, correspondingly to their frequent, external location in cell membranes [22]. Derivatized and modified polysaccharides such as water-soluble cellulosic derivatives or oxidized carboxymethylcellulose (CMC) exhibit various biological activities, such as oxygen affinity [23]. Blood anti-coagulant activity was certified for sulfonated polysaccharides [1, 24a]. At the same time, it was found that sulfonated polysaccharides have potent anti-human immunodeficiency virus activity (anti-HIV), which increases with the proportion of the amino sugar and branched units on the main chain, but decreases with the increase of deoxy sugar units [1].

Publication Source (Journal or Book title)

Modified Fibers with Medical and Specialty Applications

First Page

125

Last Page

143

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