title: Mitochondria-Targeted Approach: Remarkably Enhanced Cellular Bioactivities of TPP2a as Selective Inhibitor and Probe toward TrxR.
abstract: A 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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Baoxia
authors.initials: B
authors.lastname: Liang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Weiyan
authors.initials: W
authors.lastname: Shao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Cuige
authors.initials: C
authors.lastname: Zhu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Gesi
authors.initials: G
authors.lastname: Wen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yue
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Ruimin
authors.initials: R
authors.lastname: Wang
authors.affiliation: Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School , Shenzhen 518055, China.
authors.forename: Junmin
authors.initials: J
authors.lastname: Quan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Xianzhang
authors.initials: X
authors.lastname: Bu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; C061896:triphenylphosphine; D013880:Thioredoxin-Disulfide Reductase