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Targeting cancer cell metabolism with mitochondria-immobilized phosphorescent
cyclometalated iridium(iii) complexes
#MMPMID29780446
Cao JJ
; Tan CP
; Chen MH
; Wu N
; Yao DY
; Liu XG
; Ji LN
; Mao ZW
Chem Sci
2017[Jan]; 8
(1
): 631-640
PMID29780446
show ga
Cancer cell metabolism is reprogrammed to sustain the high metabolic demands of
cell proliferation. Recently, emerging studies have shown that mitochondrial
metabolism is a potential target for cancer therapy. Herein, four
mitochondria-targeted phosphorescent cyclometalated iridium(iii) complexes have
been designed and synthesized. Complexes 2 and 4, containing reactive
chloromethyl groups for mitochondrial fixation, show much higher cytotoxicity
than complexes 1 and 3 without mitochondria-immobilization properties against the
cancer cells screened. Further studies show that complexes 2 and 4 induce
caspase-dependent apoptosis through mitochondrial damage, cellular ATP depletion,
mitochondrial respiration inhibition and reactive oxygen species (ROS) elevation.
The phosphorescence of complexes 2 and 4 can be utilized to monitor the
perinuclear clustering of mitochondria in real time, which provides a reliable
and convenient method for in situ monitoring of the therapeutic effect and gives
hints for the investigation of anticancer mechanisms. Genome-wide transcriptional
analysis shows that complex 2 exerts its anticancer activity through metabolism
repression and multiple cell death signalling pathways. Our work provides a
strategy for the construction of highly effective anticancer agents targeting
mitochondrial metabolism through rational modification of phosphorescent iridium
complexes.
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