Photoreactivity of indirubin derivatives.
Twenty-nine analogs of indirubin, an isomer of indigo, have been synthesized to optimize its promising kinase inhibitory scaffold. These compounds being also pigmented, have been tested for their photoreactivity. Absorption maxima were between 485 nm and 560 nm. Addition of fetal calf serum induced fluorescence and time dependent absorption modifications. Appropriate illumination induced Reactive Oxygen Species (ROS) production for nineteen compounds out of twenty-nine. The relationship between fluorescence and ROS production is discussed. Six compounds showed an important toxicity on F98 cells, a murine glioma cell line. Three of these were found to be also phototoxic, as four other non-toxic compounds. All but one phototoxic compounds were detected as ROS producers by in vitro tests. Photoreactivity assessment is important to anticipate adverse reactions for compounds that might be clinically developed. The experimental assay was found to be the only way to evaluate the photoreactivity of this family of compounds since no predictive criteria on structures could be found. Combining the vascular tumor growth inhibition induced by kinase inhibitors with the massive local blood flow arrest following photodynamic treatment may be an efficient anti-cancer strategy. These data could orientate further syntheses of either non-photoreactive compounds or compounds displaying both kinase inhibitory activity and strong phototoxicity.
Olivier
David
D
HGRL, Laboratoire de Photobiologie des Cancers, Laser Department, 44093, Nantes, France.
Poincelot
Marie-Anne
MA
Douillard
Samuel
S
Lefevre
Carine
C
Moureau
Julien
J
Ferandin
Yoan
Y
Bettayeb
Karima
K
Xiao
Zhijian
Z
Magiatis
Prokopios
P
Skaltsounis
Leandros
L
Meijer
Laurent
L
Patrice
Thierry
T
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005453:Fluorescence; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology / Q000528:radiation effects; D008027:Light; D015394:Molecular Structure; D010777:Photochemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000528:radiation effects*; D011494:Protein Kinases / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000528:radiation effects; D012680:Sensitivity and Specificity; D013050:Spectrometry, Fluorescence / Q000379:methods; D013056:Spectrophotometry, Ultraviolet / Q000379:methods; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D007211:Indoles; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D011494:Protein Kinases; C027185:indirubin