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.

bioinorganic chemistry; medicinal inorganic chemistry; metals in medicine; necroptosis; ruthenium.