Organometallic Half-Sandwich Complexes of 8-Hydroxyquinoline-Derived Mannich Bases with Enhanced Solubility: Targeting Multidrug Resistant Cancer

Abstract

Drug resistance is a major obstacle in cancer treatment. Herein, four novel organometallic complexes, with the general formula [Ru(η 6 -p-cymene)(HL)Cl]Cl and [Rh(η 5 -C 5 Me 5 )-(HL)Cl]Cl, were developed to target multidrug-resistant (MDR) cancer cells, where HL denotes 8-hydroxyquinoline-derived Mannich bases (HQCl-pyr and HQCl-pip). The aim of the complexation was to obtain compounds with improved drug-like properties. The complexes were comprehensively characterized by various spectroscopic methods in terms of their structure, solution speciation and interaction with human serum albumin. The structure of [Rh(η 5 -C 5 Me 5 )(HQCl-pip)Cl]Cl was analyzed by Xray crystallography. The complexes were found to be highly stable in solution and in various biological matrices, showing enhanced solubility compared with the ligands and significant binding ability to albumin via coordination. The Rh(η 5 -C 5 Me 5 ) complexes exhibited strong cytotoxicity against MDR MES-SA/Dx5 cell lines (IC 50 = 0.19 and 0.22 μM), demonstrating high MDR-selectivity. Ganglioside-functionalized nanoparticles with the most promising ligand HQCl-pip and its Rh(η 5 -C 5 Me 5 ) complex were prepared to enhance the bioavailability. The nanocarriers showed faster drug release at acidic pH than at pH 7.4, and could retain the cytotoxicity and selectivity of the loaded compounds. The encapsulated Rh(η 5 -C 5 Me 5 ) complex of HQCl-pip has been identified as an optimal candidate for the pharmacological development of MDR-selective compounds.