Poly(N-acryl amino acids): a new class of biologically active polyanions.
Poly(N-acryl amino acids) bearing side groups with a lipophilic character or having charged functional groups (i.e. -NH(2), -COOH, -SH, -OH, and phenols) were synthesized from the radical polymerization of N-acryl amino acid monomers. Monomers were prepared from the reaction of acryloyl chloride and amino acid esters in dry solvents. Polymers of a broad molecular weight ranging from 3 000 to 60 000 Da were obtained. The polymers were optically active, and their structures were confirmed by (1)H NMR and IR spectra and elemental analysis. Hydroxyl-containing polymers were sulfated in high conversion yields by SO(3)/pyridine complex. The newly synthesized linear homopolyanions were tested for heparin-like activities: (i) inhibition of heparanase enzyme, (ii) release of basic fibroblast growth factor (bFGF) from the extracellular matrix (ECM), and (iii) inhibition of smooth muscle cell (SMC) proliferation. Polymers based on tyrosine and leucine were highly active in all three tests (microgram level). Polymers based on phenylalanine, tert-leucine, and proline were active as heparanase inhibitors and FGF release, and polymers of trans-hydroxyproline, glycine, and serine were active only as heparanase inhibitors. The polymer of cis-hydroxyproline was inactive. It was found that a net anionic charge (i.e. carboxylic acid) is essential for biological activity. Thus, methyl ester derivatives of the active polymers, zwitterionic amino acid dependent groups (lysine, histidine), and decarboxylated amino acids (tyramine, ethanolamine) were inactive. The above active polymers did not exhibit anticoagulation activity which is considered the main limitation of heparin and heparinomimetics for clinical use. These synthetic poly(N-acryl amino acids) may have potential use in the inhibition of heparanase-mediated degradation of basement membranes associated with tumor metastasis, inflammation, and autoimmunity.
Bentolila
A
A
Department of Medicinal Chemistry, School of Pharmacy, The Hebrew University of Jerusalem, Israel.
Vlodavsky
I
I
Ishai-Michaeli
R
R
Kovalchuk
O
O
Haloun
C
C
Domb
A J
AJ
D000180:Acrylic Resins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000838:Anions; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology; D019763:Heparin Lyase / Q000037:antagonists & inhibitors; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008970:Molecular Weight; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D000099166:Polyacrylamides
D000180:Acrylic Resins; D000596:Amino Acids; D000838:Anions; D000925:Anticoagulants; D004791:Enzyme Inhibitors; D016222:Fibroblast Growth Factor 2; D006493:Heparin; D019763:Heparin Lyase; D000099166:Polyacrylamides