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

Biological macromolecules are important regulators of physiological functio ns. Most of the biologically active macromolecules are charged linear polym ers like some proteins, DNA and glycosaminoglycans (GAG). Heparin, the firs t GAG applied in medicine, is a natural polyanion composed of repeating dis accharide units of glucosamine and uronic acid. The amino and hydroxyl grou ps of the glucosamine units are partially sulfated. Heparin is a potent ant icoagulant, and is also active as an antimethastatic and antiproliferative agent. Sulfatation of other polysaccharides such as laminarin yielded very potent new anticoagulans. I 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 b y the chirality of the amino acid alpha -carbon, may express heparin-like b iological activities. Homo-poly(N-acryl amino acids) were synthesized from the corresponding monomers. Polymers with different charge densities, natur e of the amino acid side group, stereoselectivity and polymeric backbone we re tested for their activity as anticoagulants, heparanase inhibition agent s, and to basic fibroblast growth factor (bFGF) 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 heparanas e inhibitors and/or as b-FGF release agents have at least ct negative charg e density of I per amino acid residue. Polymers bearing hydrophilic side ch ains that inhibited heparanase, i.e., hydroxyproline, glycine and serine, d id not release b-FGF fi om ECM. The absence of high acidic sulfate-ester gr oups existing in heparin (hydrophilic) must be compensated by some kind of lipophilic interactions between the polyanion and b-FGF in order to effecti vely compete with heparan sulfate proteogly canes, causing its release from ECM. Heparanase inhibitors may have clinical applications in preventing tu mor metastasis and inflammatory/autoimmune processes due to the involvement of this enzyme in the extravasation of blood-borne tumor cells and activat ed cells of the immune system. Molecules that release ECM-bound b-FGF may b e applied to accelerate neovascularization and tissue repair. Copyright (C) 2000 John Wiley & Sons, Ltd.