Photosensitization by imatinib. A photochemical and photobiological study of the drug and its substructures.

Abstract

Imatinib (IMT) is a promising tyrosine kinase inhibitor used in the treatment of some types of human cancer. It constitutes a successful example of rational drug design based on the optimization of the chemical structure to reach an improved pharmacological activity. Cutaneous reactions, such as increased photosensitivity or pseudoporphyria, are among the most common nonhematological IMT side effects; however, the molecular bases of these clinical observations have not been determined. Thus, to gain insight into the IMT photosensitizing properties, we addressed its photobehavior together with that of its potentially photoactive anilino-pyrimidine and pyridyl-pyrimidine fragments. In this context, steady-state and time-resolved fluorescence as well as laser flash photolysis experiments have been conducted, and the DNA photosensitization potential has been investigated by means of single-strand break detection using agarose gel electrophoresis. The obtained results reveal that the drug itself and its anilino-pyrimidine fragment are not DNA photosensitizers. By contrast, the pyridyl-pyrimidine substructure displays a marked phototoxic potential, which has been associated with the generation of a long-lived triplet excited state. Interestingly, this reactive species is efficiently quenched by benzanilide, another molecular fragment of IMT. Clearly, integration of the photoactive pyridyl-pyrimidine moiety in a more complex structure strongly modifies its photobehavior, which in this case is fortunate as it leads to an improved toxicological profile. Thus, on the bases of the experimental results, direct in vivo photosensitization by IMT seems unlikely. Instead, the reported photosensitivity disorders could be related to indirect processes, such as the previously suggested impairment of melanogenesis or the accumulation of endogenous porphyrins.

• Authors: Giacomo Nardi, Virginie Lhiaubet-Vallet, Miguel A Miranda
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 27 Issue 11 Pg. 1990-5 (Nov 17 2014) ISSN: 1520-5010 [Electronic] United States
• PMID: 25275675 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• Benzamides
• DNA, Circular
• Photosensitizing Agents
• Piperazines
• Protein Kinase Inhibitors
• Pyridines
• Pyrimidines
• Imatinib Mesylate
• aniline

Topics

• Aniline Compounds (chemistry)
• Benzamides (adverse effects, chemistry)
• DNA Damage
• DNA, Circular (drug effects, radiation effects)
• Electrophoresis, Agar Gel
• Fluorescence
• Imatinib Mesylate
• Lasers
• Luminescent Measurements
• Molecular Structure
• Photochemistry
• Photolysis (drug effects)
• Photosensitizing Agents (adverse effects, chemistry)
• Piperazines (adverse effects, chemistry)
• Protein Kinase Inhibitors (adverse effects, chemistry)
• Pyridines (chemistry)
• Pyrimidines (adverse effects, chemistry)
• Spectrophotometry, Ultraviolet
• Structure-Activity Relationship