Organometallic\nHalf-Sandwich Complexes of 8‑Hydroxyquinoline-Derived\nMannich Bases with Enhanced Solubility: Targeting Multidrug Resistant\nCancer

Drug resistance is a major obstacle in cancer treatment.\nHerein,\nfour novel organometallic complexes, with the general formula [Ru(η<sup>6</sup>-<i>p</i>-cymene)(HL)Cl]Cl and [Rh(η<sup>5</sup>-C<sub>5</sub>Me<sub>5</sub>)(HL)Cl]Cl, were developed to target\nmultidrug-resistant (MDR) cancer cells, where HL denotes 8-hydroxyquinoline-derived\nMannich bases (HQCl-pyr and HQCl-pip). The aim of the complexation\nwas to obtain compounds with improved drug-like properties. The complexes\nwere comprehensively characterized by various spectroscopic methods\nin terms of their structure, solution speciation and interaction with\nhuman serum albumin. The structure of [Rh(η<sup>5</sup>-C<sub>5</sub>Me<sub>5</sub>)(HQCl-pip)Cl]Cl was analyzed by X-ray crystallography.\nThe complexes were found to be highly stable in solution and in various\nbiological matrices, showing enhanced solubility compared with the\nligands and significant binding ability to albumin via coordination.\nThe Rh(η<sup>5</sup>-C<sub>5</sub>Me<sub>5</sub>) complexes\nexhibited strong cytotoxicity against MDR MES-SA/Dx5 cell lines (IC<sub>50</sub> = 0.19 and 0.22 μM), demonstrating high MDR-selectivity.\nGanglioside-functionalized nanoparticles with the most promising ligand\nHQCl-pip and its Rh(η<sup>5</sup>-C<sub>5</sub>Me<sub>5</sub>) complex were prepared to enhance the bioavailability. The nanocarriers\nshowed faster drug release at acidic pH than at pH 7.4, and could\nretain the cytotoxicity and selectivity of the loaded compounds. The\nencapsulated Rh(η<sup>5</sup>-C<sub>5</sub>Me<sub>5</sub>) complex\nof HQCl-pip has been identified as an optimal candidate for the pharmacological\ndevelopment of MDR-selective compounds.