EFFECTS OF MULTIDRUG-RESISTANCE (MDR1) P-GLYCOPROTEIN EXPRESSION LEVELS AND COORDINATION METAL ON THE CYTOTOXIC POTENCY OF MULTIDENTATE (N4O2) HYLENEDIAMINE)BIS[PROPYL(R-BENZYLIMINO)]METAL(III) CATIONS

Enhanced mitochondrial transmembrane potentials in tumor cells have be en proposed to confer tumor-selective-targeting properties to modestly lipophilic monocationic compounds. To explore the potential cytotoxic activity of lipophilic cationic metallopharmaceuticals containing a h ighly flexible hexadentate N4O2 Schiff-base phenolic ligand, we first synthesized precursors H(3)Mabi (1) and H(3)DMabi (2) by condensation of an appropriate linear tetraamine with substituted salicylaldehydes. The desired N4O2 ligands, (ethylenediamine)-N,N'-bis[propyl[(2-hydrox y-3- methoxybenzyl)imino]] and )-N,N'-bis[propyl[(2-hydroxy-4,6-dimeth oxybenzyl)- imino]] (R-ENBPI), were obtained by cleavage of the imidaz olidine ring, and their corresponding monocationic complexes were prod uced by reaction with appropriate hydrated salts or acetylacetonates o f AI(III), Fe(III), Ga(III), and In(III). All complexes were stable to neutral hydrolysis. In human epidermal carcinoma KB-3-1 cells, cytoto xic potencies of racemic mixtures of these complexes were in the low m icromolar range and, for a given ligand, depended on the identity of t he coordinating central metal. The active 4,6-dimethoxy-ENBPI complexe s were more potent than their 3-methoxy analogs, while the free ligand s and metal(III) ions showed little or no cytotoxic activity. Furtherm ore, in colchicine-selected KB-8-5 multidrug resistant (MDR) cells, mo dest cellular expression of human MDR1 P-glycoprotein conferred protec tion from the cytotoxic activities of AI(III), Fe(III), and Ga(III) R- ENBPI complexes indicating that these complexes were recognized as tra nsport substrates by the P-glycoprotein efflux transporter. However, t he 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 wer e capable of distinguishing R-ENBPI complexes formed of the same ligan ds with different metals. Furthermore, selected R-ENBPI metal(III) com plexes may be useful as novel anticancer metallopharmaceuticals.