Evaluation of 5-hydroxy-1,4-naphthoquinone-cobalt(III) complexes for hypoxia-activated drug delivery

Abstract

Three novel Py₂N_2-cobalt(III) complexes with the 5-hydroxy-1,4-naphthoquinone nuclei (NQ) were evaluated as potential hypoxia-activated anticancer prodrugs. The complexes were synthesized and fully characterized by IR and UV-Visible spectroscopies, ESI mass spectrometry and CHN elemental analysis. Structural information was obtained from density functional theory (DFT) calculations. Cyclic voltammetry analysis in acetonitrile indicates that the ligand substituents (H, CH₃ and p-tolylthio) do not have a relevant effect on the Co³⁺/Co²⁺ redox potential. Reactions with ascorbic acid in phosphate buffers were performed to simulate redox activation of the complexes in biological media. Fast and irreversible dissociation of the NQ ligands was observed for all complexes upon Co³⁺/Co²⁺ reduction. Cytotoxic activity of complexes 1 and 3 was evaluated in tumor cells (HT-29 and HCT-116) under hypoxic and normoxic conditions.