Enantioselective release of 5-fluorouracil from N-(2-hydroxypropyl)methacrylamide-based copolymers via lysosomal enzymes.
Water soluble copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) containing oligopeptide side chains terminated in an alpha-substituted glycine derivative of the anticancer compound 5-fluorouracil (5-FU) were synthesized by a new facilitated synthetic route and studied for their ability to release free 5-FU in the presence of lysosomal enzyme preparations. In addition, the properties of the low molecular weight alpha-substituted glycine derivatives were studied in the presence of lysosomal enzyme preparations and leucine aminopeptidase. The results revealed that (1) the stereochemistry (L vs D) of the alpha-substituted glycine derivative, (2) the hydrophobicity (Ala vs Leu) of the penultimate amino acid residue relative to the alpha-substituted glycine derivative, and (3) the total length of the oligopeptide sequence spacer (tetrapeptide vs hexapeptide) terminated in the alpha-substituted glycine derivative and the polymer carrier all directly influence the enzymatically catalyzed release of free 5-FU.
Putnam
D
D
Department of Pharmaceutics, University of Utah, Salt Lake City 84112, USA.
Kopecek
J
J
D000595:Amino Acid Sequence; D000818:Animals; D010450:Endopeptidases / Q000378:metabolism*; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000378:metabolism*; D005998:Glycine; D007202:Indicators and Reagents; D007700:Kinetics; D007931:Leucyl Aminopeptidase / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy; D008433:Mathematics; D008689:Methacrylates; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D008689:Methacrylates; D009842:Oligopeptides; D011355:Prodrugs; D010450:Endopeptidases; D007931:Leucyl Aminopeptidase; D005998:Glycine; D005472:Fluorouracil; C032802:hydroxypropyl methacrylate