Mitochondria-targeting indolizino[3,2-c]quinolines as novel class of photosensitizers for photodynamic anticancer activity.
Eur J Med Chem
; 148: 116-127, 2018 Mar 25.
Article
en En
| MEDLINE
| ID: mdl-29454916
ABSTRACT
To achieve efficient photodynamic activity, substantial effort has been dedicated to precise control of the intracellular localization of current photosensitizers (PSs). Given the extremely small radius of action of singlet oxygen, the direct targeting of PSs to the mitochondria is expected to greatly enhance the photodynamic therapy (PDT) activity. Here, we report mitochondria-targeting 6-(furan-2-yl)- and 6-(thiophen-2-yl) indolizino[3,2-c]quinolines (IQs) as novel PSs. IQ derivatives containing 5-membered heterocyclic aromatic rings were synthesized, and their photophysical properties as PSs were characterized. The anticancer potentials of 2a-2f were investigated using various cancer cell lines, and they exhibited dose-dependent and light exposure time-dependent cytotoxicity. Among the synthesized compounds, 2b, which contains a furan ring, showed dual functions as an imaging probe as well as a PS. Real-time confocal fluorescence images revealed the mitochondrial localization of 2b as a primary site of photodamage in live cells. Targeted reactive oxygen species (ROS)-generation capabilities and the photoinduced DNA cleavage of IQs led to mitochondrial dysfunction and photoinduced apoptosis via the intrinsic pathway. 3D RI tomograms of individual live HeLa cells treated with 2b showed that the progress of photoinduced apoptosis was affected by the PS concentration and light irradiation time. The studied IQs (2b, 2d, and 2e) are expected to serve as a new class of heavy-atom-free PSs with low molecular weights less than 350.
Palabras clave
Texto completo:
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Banco de datos:
MEDLINE
Asunto principal:
Fotoquimioterapia
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Quinolinas
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Fármacos Fotosensibilizantes
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Mitocondrias
Límite:
Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article