Effects of Multidrug Resistance (MDR1) P-Glycoprotein Expression Levels and Coordination Metal on the Cytotoxic Potency of Multidentate (N4O2) (Ethylenediamine)bis[propyl(R-benzylimino)]metal(III) Cations

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Abstract
Enhanced mitochondrial transmembrane potentials in tumor cells have been proposed to confer tumor-selective-targeting properties to modestly lipophilic monocationic compounds. To explore the potential cytotoxic activity of lipophilic cationic metallopharmaceuticals containing a highly flexible hexadentate N4O2 Schiff-base phenolic ligand, we first synthesized precursors H3Mabi (1) and H3DMabi (2) by condensation of an appropriate linear tetraamine with substituted salicylaldehydes. The desired N4O2 ligands, (ethylenediamine)-N,N'-bis[propyl[(2-hydroxy-3-methoxybenzyl)imino]] and (ethylenediamine)-N,N'-bis[propyl[2-hydroxy-4,6-dimethoxybenzyl)-imino]] (R-ENBPI), were obtained by cleavage of the imidazolidine ring, and their corresponding monocationic complexes were produced by reaction with appropriate hydrated salts or acetylacetonates of Al(III), Fe(III), Ga(III), and In(III). All complexes were stable to neutral hydrolysis. In human epidermal carcinoma KB-3-1 cells, cytotoxic potencies of racemic mixtures of these complexes were in the low micromolar range and, for a given ligand, depended on the identity of the coordinating central metal. The active 4,6-dimethoxy-ENBPI complexes were more potent than their 3-methoxy analogs, while the free ligands and metal(III) ions showed little or no cytotoxic activity. Furthermore, in colchicine-selected KB-8-5 multidrug resistant (MDR) cells, modest cellular expression of human MDR1 P-glycoprotein conferred protection from the cytotoxic activities of Al(III), Fe(III), and Ga(III) R-ENBPI complexes indicating that these complexes were recognized as transport substrates by the P-glycoprotein efflux transporter. However, the cytotoxic activities of the corresponding In(III) complexes, while among the lowest in potencies, were also not altered by expression of MDR1 P-glycoprotein. Thus, for the Group III elements, human cells were capable of distinguishing R-ENBPI complexes formed of the same ligands with different metals. Furthermore, selected R-ENBPI metal(III) complexes may be useful as novel anticancer metallopharmaceuticals.