Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1997-10-28
2000-11-07
Wilson, James O.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 2, 514 24, 514 25, 514 53, 514 61, 536 41, 536 59, 536109, 536118, A61K 31715, A01N 4304
Patent
active
061437301
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to sulfated oligosaccharides, their preparation and use as anti-angiogenic, anti-metastatic and/or anti-inflammatory agents.
BACKGROUND TO THE INVENTION
Heparan sulfates belong to the glycosaminoglycan family of polysaccharides. They are present in most multicellular animals and have a ubiquitous distribution, being expressed on the cell surface and in the extracellular matrices (ECM) of most tissues (1, 2). Heparan sulfates usually exist as proteoglycans and there has been considerable progress in sequencing and cloning the core polypeptides of the molecule. So far, for example, at least eight different heparan sulfate proteoglycan (HSPG) core polypeptides have been identified on the cell surface (3).
Initially HSPGs were considered to play largely a structural role on the cell surface and in the ECM. However, heparan sulfate chains exhibit remarkable structural diversity (2, 4) which suggests that they may provide important signalling information for many biological processes. Thus, although heparan sulfate chains are initially synthesised as a simple alternating repeat of glucuronosyl and N-acetylglucosaminyl residues joined by .beta.1-4 and .alpha.1-4 linkages there are many subsequent modifications. The polysaccharide is N-deacetylated and N-sulfated and subsequently undergoes C5 epimerisation of glucuronosyl units to iduronosyl units, and various O-sulfations of the uronosyl and glucosaminyl residues. The variability of these modifications allows for some thirty different disaccharide sequences which, when arranged in different orders along the heparan sulfate chain, can theoretically result in a huge number of different heparan sulfate structures. In this regard, the anticoagulant polysaccharide heparin, present only in mast cell granules, represents an extreme form of heparan sulfate where epimerisation and sulfation have been maximised. Most heparan sulfates contain short stretches of highly sulfated residues joined by relatively long stretches of non-sulfated units.
There is now clear evidence that heparan sulfates play a critical role in a wide range of biological processes (2-4). In particular, they can act as ligands for adhesion molecules involved in cell--cell interactions (5, 6), participate in cell-ECM interactions (5, 6) and act as essential cell surface receptors for growth factors such as basic fibroblast growth factor (bFGF) (7, 8) and vascular endothelial growth factor (VEGF) (9). HSPGs are also a key component of basement membranes, which represent a major barrier to cell migration (10). Basement membrane barriers can only be breached when cells deploy a range of degradative enzymes (11) including an endoglycosidase, termed heparanase, which cleaves heparan sulfate chains (12, 13).
It has been shown that many of the biological processes in which heparan sulfates participate involve the recognition of unique heparan sulfate structures, with the position of the sulfates in the polysaccharide chain being of critical importance (3). For example, it has been demonstrated that defined heparan sulfate sequences are recognised by acidic and basic FGF (14-16) and cleaved by heparanases. Based on these observations, it has been an objective of the present inventors to synthesise sulfated oligosaccharides which block heparan sulfate recognition by growth factors, and inhibit cleavage of heparan sulfates by heparanases. In the case of blocking of growth factors, it was considered that low molecular weight mimics of heparan sulfate should be particularly effective, as it is now believed that cell surface heparan sulfates mediate the cross linking of growth factors bound to their receptors (17). Furthermore, sulfated oligosaccharides should be effective heparanase inhibitors by acting as non-cleavable substrates of this enzyme.
Sulfated oligosaccharides with growth factor inhibitory activity have a number of clinical uses. Heparin/heparan sulfate binding growth factors, such as bFGF and VEGF, are potent inducers of angiogenesis (18). In adults, ang
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Cowden William Butler
Parish Christopher Richard
The Australian National University
Wilson James O.
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