ABSTRACT
A series of gallium(III) amide corroles including meso-5,15-bis(pentafluorophenyl)-10-(4-Pyridinamide-phenyl)corrole gallium (III) (1-Ga), meso-5,15-bis(pentafluorophenyl)-10-(4-Furamide-phenyl)corrole gallium(III) (2-Ga) and meso-5,15-bis(pentafluorophenyl)-10-(4-Thiophenamide-phenyl)corrole gallium(III) (3-Ga) were synthesized. The interaction of these complexes with DNA and their photodynamic antitumor activities have been studied. UV spectra titration showed that these gallium(III) corroles interact with calf thymus DNA (CT-DNA) through an external binding mode. All three gallium(III) corroles can effectively generate singlet oxygen under illumination and have good photostability. Among the three gallium(III) corroles, 2-Ga exhibited excellent photodynamic antitumor activity against the tested tumor cell lines under light irradiation (625±2â nm, 0.3â mW/cm2 , 1.08â J/cm2 ). The best phototoxicity was observed by 2-Ga against HepG2 cells (IC50 =6.3±0.9), which is even better than temoporfin (IC50 =8.4±1.8). It could block HepG2 cells in the sub-G0 phase and effectively induce apoptosis of HepG2 cells under 625â nm light irradiation.
Subject(s)
Gallium , Neoplasms , Porphyrins , Gallium/pharmacology , Gallium/chemistry , Porphyrins/chemistry , DNA/chemistry , Cell Line, TumorABSTRACT
A series of halogenated gallium corroles were synthesized and characterized by UV-vis, HRMS, NMR, and FT-IR. The interaction between these gallium corroles and calf thymus DNA had been investigated by spectroscopic methods. These gallium corroles would interact with CT-DNA via an outside binding mode. The photodynamic antitumor activity in vitro of these gallium corroles toward different cell lines had also been tested. 3-Ga displayed low cytotoxicity to normal cells under both light and dark conditions but high phototoxicity to liver cancer cells HepG2. The vitro experiment results showed that 3-Ga could be efficiently absorbed by tumor cells. After light illumination, it may induce reactive oxygen species (ROS) and cause destruction of the mitochondrial membrane potential, which may finally trigger tumor cell apoptosis. Flow cytometry results showed that HepG2 cells were mainly distributed in the sub-G0 phase, which corresponds to cells with highly fragmented DNA or dead cells generally. This suggests that 3-Ga could lead to tumor cell apoptosis after light illumination.
Subject(s)
DNA/chemistry , Gallium/chemistry , Halogenation , Neoplasms/drug therapy , Photochemotherapy , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Porphyrins/chemistry , Animals , Drug Screening Assays, Antitumor , Female , Hep G2 Cells , Humans , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred BALB C , Neoplasms/metabolism , Photosensitizing Agents/toxicity , Reactive Oxygen Species/metabolism , Spectrum Analysis/methods , Toxicity Tests, AcuteABSTRACT
Three mono-hydroxy corroles 1-3 and their gallium(III) complexes Ga1-3 were synthesized, and their photodynamic antitumour activities towards breast cancer cells were investigated. All corroles showed excellent cytotoxicity against the MDA-MB-231 and 4T1 cell lines upon light irradiation at 625 nm. Ga3 exhibited excellent phototoxicity and selectivity against MDA-MB-231 cells, with an IC50 of 0.06 ± 0.03 µM and a selective index value of 1338.83 (relative to human normal Huvec cells). The performance of Ga3 was even better than that of the clinical photodynamic therapy drug m-THPC. A preliminary mechanistic investigation revealed that corrole 3 and Ga3 were mainly located in the cytoplasm. Upon irradiation, they could generate intracellular reactive oxygen to destroy the mitochondrial membrane potential and arrest the cell cycle at the sub-G1 phase. Flow cytometry revealed that corrole 3 and Ga3 induced cancer cell apoptosis after photodynamic treatment. Corrole 3 and Ga3 displayed negligible cytotoxicity in the dark. These results suggest that corrole 3 and Ga3 are promising candidates for use in the photodynamic therapy of breast cancer.
