Evaluation of dipeptide-derivatives of 5-aminolevulinic acid as precursors for photosensitizers in photodynamic therapy

Bioorg Med Chem. 2003 Apr 3;11(7):1343-51. doi: 10.1016/s0968-0896(02)00619-3.

Abstract

N-terminal-blocked and N-terminal-free pseudotripeptide Gly-Gly and Gly-Pro derivatives of 5-aminolevulinic acid (ALA) esters were synthesized as potential specific substrates for cellular peptidases and precursors for the production of the photosensitizer protoporphyrin IX (PpIX). These precursors were evaluated using human cell lines of either carcinoma or endothelial origin. N-blocked or N-free dipeptides-ALA-ethyl esters, but not tripeptides-ALA-ethyl esters (or dipeptides-ALA-ethyleneglycols,) were substrates for cellular peptidases and were metabolized to ALA. The precursors were hydrolyzed intracellularly involving serine-proteases and metalloproteases. Cell selectivity for human endothelial or carcinoma cells was observed for some of these dipeptides-ALA. Thus drugs coupled to Gly-Gly-/Gly-Pro-derivatives may selectively target defined cells in human cancer, depending on specific cellular activating pathways expressed by the cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminolevulinic Acid / analogs & derivatives*
  • Aminolevulinic Acid / chemical synthesis
  • Aminolevulinic Acid / pharmacology*
  • Cells, Cultured
  • Dipeptides / chemical synthesis*
  • Dipeptides / pharmacology*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Humans
  • Hydrolysis
  • Neprilysin / metabolism
  • Peptide Hydrolases / metabolism
  • Peptides / chemical synthesis
  • Peptides / pharmacology
  • Photochemotherapy*
  • Photosensitizing Agents / chemical synthesis*
  • Photosensitizing Agents / pharmacology*
  • Protoporphyrins / metabolism
  • Spectrometry, Fluorescence
  • Tumor Cells, Cultured

Substances

  • Dipeptides
  • Peptides
  • Photosensitizing Agents
  • Protoporphyrins
  • Aminolevulinic Acid
  • protoporphyrin IX
  • Peptide Hydrolases
  • Neprilysin