8-Hydroxyquinoline-modified ruthenium() polypyridyl complexes for JMJD inhibition and photodynamic antitumor therapy

As an ideal scaffold for metal ion chelation, 8-hydroxyquinoline (8HQ) can chelate different metal ions, such as Fe 2+ , Cu 2+ , Zn 2+ , etc. Here, by integrating 8HQ with a ruthenium( ii ) polypyridyl moiety, two Ru( ii )-8HQ complexes ( Ru1 and Ru2 ), [Ru(N-N) 2 L ](PF 6 ) 2 ( L = 2-(1 H -imidazo[4,5- f ][1,10]phenanthrolin-2-yl)quinolin-8-ol; N-N: 2,2′-bipyridine (bpy, in Ru1 ), 1,10-phenanthroline (phen, in Ru2 )) were designed and synthesized. In both complexes, ligand L is an 8HQ derivative designed to chelate the cofactor Fe 2+ of jumonji C domain-containing demethylase (JMJD). As expected, Ru1 and Ru2 could inhibit the activity of JMJD by chelating the key cofactor Fe 2+ of JMJD, resulting in the upregulation of histone-methylation levels in human lung cancer (A549) cells, and the upregulation was more pronounced under light conditions. In addition, MTT data showed that Ru1 and Ru2 exhibited lower dark toxicity, and light irradiation could significantly enhance their antitumor activity. The marked photodynamic activities of Ru1 and Ru2 could induce the elevation of reactive oxygen species (ROS), depolarization of mitochondrial membrane potential (MMP), and activation of caspases. These mechanistic studies indicated that Ru1 and Ru2 could induce apoptosis through the combination of JMJD inhibitory and PDT activities, thereby achieving dual antitumor effects. The successful design and anticancer mechanistic studies of a series of ruthenium( ii ) polypyridyl complexes with jumonji C domain-containing demethylase (JMJD) inhibitory and photodynamic therapy (PDT) activities are reported.