Synthesis and heparin-like biological activity of amino acid-based polymers

Abstract

Biological macromolecules are important regulators of physiological functions. Most of the biologically active macromolecules are charged linear polymers like some proteins, DNA and glycosaminoglycans (GAG). Heparin, the first GAG applied in medicine, is a natural polyanion composed of repeating disaccharide units of glucosamine and uronic acid. The amino and hydroxyl groups of the glucosamine units are partially sulfated. Heparin is a potent anticoagulant, and is also active as an antimethastatic and antiproliferative agent. Sulfatation of other polysaccharides such as laminarin yielded very potent new anticoagulans. It was hypothesized that macromolecules based on N-acryl L-amino acids bearing hydrophobic or charged side groups, such as NH2, COOH, SH, OH and phenols, arranged into a configuration determined by the chirality of the amino acid α-carbon, may express heparin-like biological activities. Homo-poly(N-acryl amino acids) were synthesized from the corresponding monomers. Polymers with different charge densities, nature of the amino acid side group, stereoselectivity and polymeric backbone were tested for their activity as anticoagulants, heparanase inhibition agents, and to basic fibroblast growth factor (b-FGF) release agents bound to the extracellular matrix (ECM). The type of amino acid, the polymer backbone, the charge density and distribution strongly affect the biological activity exerted by these polyanions. All polymers being active either as heparanase inhibitors and/or as b-FGF release agents have at least a negative charge density of 1 per amino acid residue. Polymers bearing hydrophilic side chains that inhibited heparanase, i.e., hydroxyproline, glycine and serine, did not release b-FGF from ECM. The absence of high acidic sulfate-ester groups existing in heparin (hydrophilic) must be compensated by some kind of lipophilic interactions between the polyanion and b-FGF in order to effectively compete with heparan sulfate proteoglycanes, causing its release from ECM. Heparanase inhibitors may have clinical applications in preventing tumor metastasis and inflammatory/autoimmune processes due to the involvement of this enzyme in the extravasation of blood-borne tumor cells and activated cells of the immune system. Molecules that release ECM-bound b-FGF may be applied to accelerate neovascularization and tissue repair. Copyright © 2000 John Wiley & Sons, Ltd.