Necroptosis Induced by Ruthenium(II) Complexes as Dual Catalytic Inhibitors of Topoisomerase I/II

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. RuII complexes were developed to act as dual catalytic inhibitors of topoisomerase I and II. Tuning of the auxiliary ligands gave complex Ru7, which targets the nucleus of cancer cells effectively, inducing cell death via necroptosis. The cell signaling pathways were investigated and the in vivo activity against drug resistant cancer was found to be excellent.