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Mitochondria-Targeted Approach: Remarkably Enhanced Cellular Bioactivities of TPP2a as Selective Inhibitor and Probe toward TrxR
journal contribution
posted on 2015-12-14, 00:00 authored by Baoxia Liang, Weiyan Shao, Cuige Zhu, Gesi Wen, Xin Yue, Ruimin Wang, Junmin Quan, Jun Du, Xianzhang BuA mitochondria-targeted
approach was developed to increase the
cellular bioactivities of thioredoxin reductase (TrxR) inhibitors.
By being conjugated with a triphenylphosphine (TPP) motif to a previously
found TrxR inhibitor 2a, the resulted compound TPP2a can target subcellular
mitochondria and efficiently inhibit cellular TrxR, leading to remarkably
increased cellular ROS level and mitochondrial apoptosis of HeLa cancer
cells. The cellular bioactivities of TPP2a, including its cytotoxicity
against a panel of cancer cell lines, dramatically elevated compared
with its parental compound 2a. The selectively and covalently interaction
of TPP2a with subcellular mitochondrial TrxR was validated by fluorescent
microscopy. Moreover, a nonspecific signal quenching coupled strategy
was proposed based on the environmentally sensitive fluorescence of
TPP2a, which makes it possible to label TrxR by removing the nonspecific
backgrounds caused by TPP2a under complex biosettings such as cellular
lysates and living cells, implicating a potential of TPP2a for TrxR-specific
labeling.