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

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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2003-04, Vol.11 (7), p.1343-1351
Main Authors: BERGER, Yann, INGRASSIA, Laurent, NEIER, Reinhard, JUILLERAT-JEANNERET, Lucienne
Format: Article
Language:English
Subjects:
Aminolevulinic Acid - analogs & derivatives
Aminolevulinic Acid - chemical synthesis
Aminolevulinic Acid - pharmacology
Biological and medical sciences
Cells, Cultured
Dipeptides - chemical synthesis
Dipeptides - pharmacology
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Humans
Hydrolysis
Medical sciences
Neprilysin - metabolism
Peptide Hydrolases - metabolism
Peptides - chemical synthesis
Peptides - pharmacology
Photochemotherapy
Photoradiation therapy and photosensitizing agent
Photosensitizing Agents - chemical synthesis
Photosensitizing Agents - pharmacology
Protoporphyrins - metabolism
Spectrometry, Fluorescence
Treatment with physical agents
Treatment. General aspects
Tumor Cells, Cultured
Tumors
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Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(02)00619-3