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

  • Angew Chem Int Ed Engl. 2020 Sep 14;59(38):16631-16637. doi: 10.1002/anie.202006089.
Kai Xiong  1 ,  Chen Qian  1 ,  Yixian Yuan  1 ,  Lin Wei  2 ,  Xinxing Liao  1 ,  Liting He  1 ,  Thomas W Rees  1 ,  Yu Chen  1 ,  Jian Wan  2 ,  Liangnian Ji  1 ,  Hui Chao  1  3
Affiliations
  • 1. MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P. R. China.
  • 2. College of Chemistry, Central China Normal University, Wuhan, 430079, P. R. China.
  • 3. College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, 518071, P. R. China.
PMID: 32533618 DOI: 10.1002/anie.202006089
Abstract

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.

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