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Necroptosis Induced by Ruthenium(II) Complexes as Dual Catalytic Inhibitors of Topoisomerase I/II
Author(s) -
Xiong Kai,
Qian Chen,
Yuan Yixian,
Wei Lin,
Liao Xinxing,
He Liting,
Rees Thomas W.,
Chen Yu,
Wan Jian,
Ji Liangnian,
Chao Hui
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202006089
Subject(s) - necroptosis , cancer cell , chemistry , topoisomerase , programmed cell death , ligand (biochemistry) , ruthenium , apoptosis , cancer research , microbiology and biotechnology , in vitro , cancer , biochemistry , biology , catalysis , receptor , genetics
Inducing necroptosis in cancer cells is an effective approach to circumvent drug‐resistance. Metal‐based triggers have, however, rarely been reported. Ruthenium(II) complexes containing 1,1‐(pyrazin‐2‐yl)pyreno[4,5‐e][1,2,4]triazine were developed with a series of different ancillary ligands ( Ru1 ‐ 7 ). The combination of the main ligand with bipyridyl and phenylpyridyl ligands endows Ru7 with superior nucleus‐targeting properties. As a rare dual catalytic inhibitor, Ru7 effectively inhibits the endogenous activities of topoisomerase (topo) I and II and kills cancer cells by necroptosis. The cell signaling pathway from topo inhibition to necroptosis was elucidated. Furthermore, Ru7 displays significant antitumor activity against drug‐resistant cancer cells in vivo. To the best of our knowledge, Ru7 is the first Ru‐based necroptosis‐inducing chemotherapeutic agent.