Highly cytotoxic substitutionally inert rhodium(III) tris(chelate) complexes: DNA binding modes and biological impact on human cancer cells

The antiproliferative properties and cellular impact of novel substitutionally inert rhodium(III) complexes of the types [Rh{(CH3)2 NCS2}2(pp)]Cl 3–5 (pp = 5,6-Me2phen, dpq, dppz) and OC-6-23-[Rh(2-S-py)2(pp)]Cl 6 and 7 (2-S-py = pyridine-2-thiolate; pp = dpq, dppz) have been investigated for the adherent human cancer cell lines MCF-7 and HT-29 and for non-adherent Jurkat cells. Whereas CD and viscosity measurements indicate that the polypyridyl ligands of 4 and 5 intercalate into CT DNA, this is not the case for the analogous pyridine-2-thiolate complexes 6 and 7. Complexes 3–7 all exhibit a high antiproliferative activity towards MCF-7 and HT-29 cells, with IC50 values in the range 0.055–0.285 μM. As established by online monitoring with a cell-based sensor chip, the highly cytostatic complex 6 (IC50 = 0.059 and 0.078 μM) invokes an immediate concentration-dependent reduction of MCF-7 cell respiration and a time-delayed decrease in cellular impedance, which can be ascribed to the induction of cell death. Annexin V/PI assays demonstrated that 6 also has a pronounced antiproliferative activity towards Jurkat cells and that it invokes extensive apoptosis and high concentrations of reactive oxygen species in these leukemia cells. The observation of a dose-dependent inhibition of the oxygen consumption of isolated mice mitochondria indicates the involvement of an intrinsic mitochondrial pathway in this process.

Graphical abstractAlthough substitutionally inert, monocationic Rh(III) complexes such as [Rh{(CH3)2NCS2}2(dppz)]+ are potent cytostatic agents towards human cancer cells with IC50 values in the low nanomolar range. They induce high levels of reactive oxygen species in leukemia cells and invoke apoptosis via the intrinsic mitochondrial pathway.Figure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights► Substitutionally inert rhodium(III) complexes are potent cytostatic agents ► Up to 152 fold uptake in human cancer cells. ► Induction of high levels of reactive oxygen species and subsequent apoptosis. ► Dose-dependent inhibition of mitochondrial respiration.