Fine-Tuning the Activation Mode of an 1,3-Indandione-Based Ruthenium(II)-Cymene Half-Sandwich Complex by Variation of Its Leaving Group

Stephan Mokesch; Daniela Schwarz; Michaela Hejl; Matthias H M Klose; Alexander Roller; Michael A Jakupec; Wolfgang Kandioller; Bernhard K Keppler

doi:10.3390/molecules24132373

Fine-Tuning the Activation Mode of an 1,3-Indandione-Based Ruthenium(II)-Cymene Half-Sandwich Complex by Variation of Its Leaving Group

Molecules. 2019 Jun 27;24(13):2373. doi: 10.3390/molecules24132373.

Authors

Stephan Mokesch¹, Daniela Schwarz¹, Michaela Hejl¹, Matthias H M Klose¹, Alexander Roller¹, Michael A Jakupec^{1

2}, Wolfgang Kandioller^{3

4}, Bernhard K Keppler^{1

2}

Affiliations

¹ Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A-1090 Vienna, Austria.
² Research Cluster "Translational Cancer Therapy Research", University of Vienna, Waehringer Straße 42, A-1090 Vienna, Austria.
³ Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A-1090 Vienna, Austria. wolfgang.kandioller@univie.ac.at.
⁴ Research Cluster "Translational Cancer Therapy Research", University of Vienna, Waehringer Straße 42, A-1090 Vienna, Austria. wolfgang.kandioller@univie.ac.at.

Abstract

Fine-tuning of the properties of a recently reported 1,3-indandione-based organoruthenium complex is attempted to optimize the stability under physiological conditions. Previous work has shown its capacity of inhibiting topoisomerase IIα; however, fast aquation leads to undesired reactions and ligand cleavage in the blood stream before the tumor tissue is reached. Exchange of the chlorido ligand for six different N-donor ligands resulted in new analogs that were stable at pH 7.4 and 8.5. Only a lowered pH level, as encountered in the extracellular space of the tumor tissue, was capable of aquating the complexes. The 50% inhibitory concentration (IC₅₀) values in three human cancer cell lines differed only slightly, and their dependence on the utilized leaving group was smaller than what would be expected from their differences in cellular accumulation, but in accordance with the very minor variation revealed in measurements of the complexes' lipophilicity.

Keywords: anticancer drugs; half-sandwich complexes; leaving group variation; ruthenium(II)–arene complexes.

MeSH terms

Cell Line, Tumor
Coordination Complexes / chemical synthesis*
Coordination Complexes / chemistry
Coordination Complexes / pharmacology
Cymenes / chemical synthesis*
Cymenes / chemistry
Cymenes / pharmacology
Drug Screening Assays, Antitumor
Humans
Inhibitory Concentration 50
Molecular Structure
Ruthenium / chemistry*

Substances

Coordination Complexes
Cymenes
Ruthenium