An 8-hydroxyquinoline-proline hybrid with multidrug resistance reversal activity and solution chemistry of its half-sandwich organometallic Ru and Rh complexes
Herein the design and synthesis of a new 8-hydroxyquinoline derivative, (S)-5-chloro-7-((proline-1-yl)methyl)8-hydroxyquinoline (HQCl-Pro) with good water solubility and multidrug resistance reversal activity are reported. In this work the proton dissociation processes of HQCl-Pro and its complex formation with [Rh(η5-C5Me5)(H2O)3]2+, [Ru(η6-p-cymene)(H2O)3]2+ and [Ru(η6-toluene)(H2O)3]2+ were investigated by the combined use of pH-potentiometry, UV-visible spectrometry and 1H NMR spectroscopy. Our results revealed prominent solution stability of the complexes in all cases. The lipophilicity of the complexes increased with the chloride ion concentration, and the complexes showed moderate logD values (-0.8 ‒ +0.4) at pH 7.4 at all tested Cl- concentrations. The formation of mixed hydroxido complexes from the aqua complexes was characterized by relatively high pKa values (8.45 – 9.62 in chloride-free medium). Complexation processes are much slower with the Ru(η6-arene) triaqua cations than with [Rh(η5-C5Me5)(H2O)3]2+. Both the pKa values and the H2O/Cl− exchange constants of the Ru-complexes are lower by 0.5–1.0 orders of magnitude than the Rh analogue. Arene loss (p-cymene and toluene) and oxidation was found in the case of Ru-complexes when ligand excess of HQCl-Pro and aromatic (N,N) bidentate ligands were added. Cytotoxicity and antiproliferative effect of HQCl-Pro and its complexes were assayed in vitro. In contrast with the structurally familiar 8-hydroxyquinoline, HQCl-Pro and its Rh(η5-C5Me5) complex were somewhat more effective against drug resistant Colo 320 adenocarcinoma human cells compared to the drug sensitive Colo 205 cells. The Ru- and Rh-complexes showed similar metal uptake level after 4 h, while longer incubation time resulted in higher cellular Rh concentration.