Three novel pyrimidinylhydrazones substituted at either the aromatic moiety or at the imine carbon atom were synthesized and characterized by standard analytical methods. All compounds were found to be toxic in the micro- to submicromolar range against a diverse panel of cancer cell lines including multidrug resistant (MDR) derivatives expressing P-glycoprotein (Pgp). UV-visible spectrophotometry experiments demonstrated that the most active compound (3) forms highly stable complexes with iron(III) and copper(II) in a wide pH range with a stronger preference towards iron(III). The redox activity of the iron and copper complexes of ligand 3 was investigated using cyclic voltammetry and was tested with cellular reductants. The impact of reactive oxygen species (ROS) on the mechanism of toxicity was assessed using the ROS-sensitive cell permeable dye 2',7'-dichlorofluorescin diacetate (DCFDA). Our results demonstrate that the studied pyrimidinylhydrazones form redox-active iron and copper complexes that are capable of producing intracellular ROS, which might lead to cellular damage and cell death in cancer cells regardless of their resistance status.
Keywords: Arylhydrazones; Metal complexes; Multidrug resistance; Reactive oxygen species; Stability constants.
Copyright © 2014. Published by Elsevier Inc.