Anticancer Potential of Camalexin-Derived Ru(II) Metallacycles

Abstract

Camalexin, a primary indole-analogous phytoalexin from Arabidopsis thaliana and other crucifers, inhibits the proliferation of various cancer cells. In this contribution, the synthesis and characterization of camalexin-derived Ru(II) half-sandwich complexes are described. Formation and sufficient purity of the complexes were confirmed by 1H-, 13C- and 2D-NMR techniques, X-ray or 3D electron diffractometry, high-resolution-mass-spectrometry (HRMS) and elemental analysis. Additionally, the stability in aqueous solution was studied under pseudophysiological conditions, revealing sufficient stability for further biological studies. Investigating the in vitro anticancer potency by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) and resazurin assays in four human cancer cell lines revealed IC50 values in the (mostly low) micromolar range. Tests for the capacity of generating reactive oxygen species (ROS) in the leukemic HL60 cell line identified one derivative with exceptionally high ROS induction via a 2′,7′-dichlorofluorescin diacetate (DCFH-DA)-based approach. While increased ROS levels were not decisive for cell death induction, cytotoxic activity of the complexes was associated with mitochondrial membrane depolarization and functional perturbation. Lastly, the ability of the complexes to induce apoptosis was investigated, with the complexes showing remarkable effects, while the free ligands exhibited hardly any signs of apoptosis induction.