Synthesis and DNA-binding properties of apoptosis-inducing cytotoxic half-sandwich rhodium(III) complexes with methyl-substituted polypyridyl ligands

Half-sandwich organorhodium(III) complexes of the type [(η5-C5Me5)RhCl(pp)] (CF3SO3) containing polypyridyl ligands (pp) represent a promising class of cytostatic agents. Replacement of the polypyridyl ligands of complexes 1 (pp = phen) and 6 (pp = dppz) by methyl-substituted derivatives in 2–5 (pp = 4-Mephen, 5-Mephen, 4,7-Me2phen, 5,6-Me2phen) and 7 (pp = Me2dppz) leads to a significant improvement in their antiproliferative activity towards human MCF-7 and HT-29 cancer cells. For instance, the IC50 value towards HT-29 cells decreases from 4.3 ± 0.2 μM for 6 to 0.98 ± 0.49 μM for complex 7. In contrast, no activity (IC50 > 100 μM) was observed for the HOOC and n-BuNHCO substituted dppz complexes 8 and 9. UV/vis, CD and NMR spectra for mixtures of complexes 7–9 with CT DNA were in accordance with intercalation of the substituted dppz ligands between the base pairs of the double helix and direct evidence for this binding mode was also provided by a 2D NOESY study for complex 7 with the hexanucleotide d(5′-CGTCGG-3′). Each of the methyl-substituted phen complexes 2–5 is significantly more active towards immortalized HEK-293 cells (IC50 values 0.40 ± 0.02 to 0.94 ± 0.02 μM) than towards the cancer cells. Flow cytometric measurements of DNA fragmentation in BJAB cells following an incubation period of 72 h with 1, 5 and 6 indicate that the complexes induce specific apoptotic cell death in the non-adherent lymphoma cells.

Organorhodium(II) complexes of the type [(η5-C5Me5)RhCl(pp)]Cl represent a promising class of cytostatic agents that induce apoptotic cell death via the intrinsic mitochondrial pathway. Methyl substitution of the polypyridyl(pp) ligands phenanthroline and dppz leads to improved antiproliferative activity.Figure optionsDownload as PowerPoint slideResearch highlights
► Half-sandwich organorhodium(III) complexes with substituted phenanthroline ligands invoke apoptosis.
► Cytotoxicity towards human cancer cells improves on methyl substitution.
► Electron-withdrawing substituents reduce cytotoxicity.
► NOESY studies confirm DNA intercalation for the larger methyl-substituted dppz ligand.