Coordination of Ru(II)-Arene Fragments to Dipyridophenazine Ligands Leads to the Modulation of Their In Vitro and In Vivo Anticancer Activity

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • Stefan Nikolić
  • Vladimir Kushnarev
  • Samah Mutasim Alfadul
  • Dalibor Stanković
  • Yaroslav I. Kraynik
  • Sanja Grgurić-Šipka

Related Research Unit(s)

Detail(s)

Original languageEnglish
Pages (from-to)8188–8199
Journal / PublicationInorganic Chemistry
Volume62
Issue number21
Online published18 May 2023
Publication statusPublished - 29 May 2023

Abstract

Despite extensive research on the anticancer properties of Ru complexes with dipyrido[3,2-a:2′,3′-c]phenazine (dppz) ligands, their in vivo efficacy is rarely investigated. Aiming to understand whether the coordination of certain half-sandwich Ru(II)-arene fragments might improve the therapeutic potential of dppz ligands, we prepared a series of Ru(II)-arene complexes with the general formula [(η6-arene)Ru(dppz-R)Cl]PF6, where the arene fragment was benzene, toluene, or p-cymene and R was -NO2, -Me, or -COOMe. All compounds were fully characterized by 1H and 13C NMR spectroscopy and high-resolution ESI mass-spectrometry, and their purity was verified by elemental analysis. The electrochemical activity was investigated using cyclic voltammetry. The anticancer activity of dppz ligands and their respective Ru complexes was assessed against several cancer cell lines, and their selectivity toward cancer cells was assessed using healthy MRC5 lung fibroblasts. The substitution of benzene with a p-cymene fragment resulted in a more than 17-fold increase of anticancer activity and selectivity of Ru complexes and significantly enhanced DNA degradation in HCT116 cells. All Ru complexes were electrochemically active in the biologically accessible redox window and were shown to markedly induce the production of ROS in mitochondria. The lead Ru-dppz complex significantly reduced tumor burden in mice with colorectal cancers without inducing liver and kidney toxicity. © 2023 American Chemical Society.

Citation Format(s)

Coordination of Ru(II)-Arene Fragments to Dipyridophenazine Ligands Leads to the Modulation of Their In Vitro and In Vivo Anticancer Activity. / Nikolić, Stefan; Arakelyan, Jemma; Kushnarev, Vladimir et al.
In: Inorganic Chemistry, Vol. 62, No. 21, 29.05.2023, p. 8188–8199.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review