Interactions of IOX1, a histone demethylase inhibitor, with essential metal ions, albumin, and its clay-based nanoformulation

Abstract

Herein, the chemical properties of 5-carboxy-8-hydroxyquinoline (IOX1), a histone lysine demethylase KDM4 inhibitor, were comprehensively characterized in aqueous solution, including its complex formation equilibria with essential metal ions such as Fe(II), Fe(III), and Cu(II). IOX1 shows the following metal ion preference at pH 7.4: Fe(II) < Fe(III) < Cu(II). Compared to 2oxoglutarate, the natural substrate of KDM4, IOX1 exhibits a higher affinity for both iron ions. The Rh(III)(η⁵-C₅Me₅) (RhCp*) complex of IOX1 was synthesized and characterized by UV-visible, NMR, and mass spectrometry techniques, showing high stability in aqueous solution without the dissociation of IOX1 over a wide pH range and strong interaction with human serum albumin. To access the potential benefits of nanocapsulation, IOX1-loaded anionic clay (LDH) nanoparticles (LDH/IOX1) were successfully synthesized. The anticancer properties of IOX1, its RhCp* complex, and LDH/IOX1 were evaluated in human cancer cell lines. The RhCp* complex exhibited a greater antiproliferative activity toward Colo205 cells than IOX1 alone, and all tested compounds significantly decreased the mitochondrial membrane potential. The LDH/IOX1 system also showed pronounced cytotoxicity on A549 cells, accompanied by strong mitochondrial impairment, indicating the potential of nanocapsulation of small-molecule enzyme inhibitors in cancer therapy.