Poly(N-acryl amino acids): A new class of biologically active polyanions

Poly(N-acryl amino acids) bearing side groups with a lipophilic character o r having charged functional groups (i.e. -NH2, -COOH, -SH, -OH, and phenols ) were synthesized from the radical polymerization of N-acryl amino acid mo nomers. Monomers were prepared from the reaction of acryloyl chloride and a mino acid esters in dry solvents. Polymers of a broad molecular weight rang ing from 3 000 to 60 000 Da were obtained. The polymers were optically acti ve, and their structures were confirmed by H-1 NMR and IR spectra and eleme ntal analysis. Hydroxyl-containing polymers were sulfated in high conversio n yields by SO3/pyridine complex. The newly synthesized linear homopolyanio ns were tested for heparin-like activities: (i) inhibition of heparanase en zyme, (ii) release of basic fibroblast growth factor (bFGF) from the extrac ellular matrix (ECM), and (iii) inhibition of smooth muscle cell (SMC) prol iferation. Polymers based on tyrosine and leucine were highly active in all three tests (microgram level). Polymers based on phenylalanine, tert-leuci ne, and proline were active as heparanase inhibitors and FGF release, and p olymers of trans-hydroxyproline, glycine, and serine were active only as he paranase inhibitors. The polymer of cis-hydroxyproline was inactive. It was found that a net anionic charge (i.e. carboxylic acid) is essential for bi ological activity. Thus, methyl ester derivatives of the active polymers, z witterionic amino acid pendent groups (lysine, histidine), and decarboxylat ed amino acids (tyramine, ethanolamine) were inactive. The above active pol ymers did not exhibit anticoagulation activity which is considered the main limitation of heparin and heparinomimetics for clinical use. These synthet ic poly(N-acryl amino acids) may have potential use in the inhibition of he paranase-mediated degradation of basement membranes associated with tumor m etastasis, inflammation, and autoimmunity.