New heteroleptic lanthanide complexes as multimodal drugs: Cytotoxicity studies, apoptosis, cell cycle analysis, DNA interactions, and protein binding
Alexandra‐Cristina Munteanu, Mihaela Georgiana Musat, Mirela Mihăilă, Mihaela Badea, Rodica Olar, George Mihai Nițulescu, Flavian Ștefan Rădulescu, Lorelei Irina Braşoveanu, Valentina Uivaroşi
Abstract
We report herein the synthesis and characterization of four new heteroleptic complexes of Sm(III), Eu(III), Gd(III), and Tb(III) with the natural flavonoid 5‐hydroxyflavone (primuletin) and 1,10‐phenanthroline. According to the physicochemical characterization, the mononuclear complexes correspond to the general formula [Ln(OH) 2 L 1 L 2 ]· n H 2 O , where L 1 = C 15 H 9 O 3 (deprotonated 5‐hydroxyflavone) and L 2 = C 12 H 8 N 2 (1,10‐phenanthroline), Ln is the lanthanide cation, and n = 4 for Sm(III), 3.5 for Eu(III), 2 for Gd(III), and 3 for Tb(III). A six‐coordinated distorted octahedron geometry was proposed for the complexes, and density functional theory (DFT) studies were used to calculate their optimized geometry. Cytotoxicity was studied using MTS assay on cervical, colorectal, colon, breast, and ovarian adenocarcinoma cell lines. Flow cytometry data were consistent with apoptotic cell death and disruption of the cell cycle in cervical and colon cancer cells. As a means to investigate the mechanism underlying the cytotoxic effects, the abilities of the complexes to interact with calf thymus DNA, human serum albumin, and transferrin have also been assessed. According to experimental and computational studies, the four lanthanide complexes act as DNA intercalators and bind strongly to serum proteins.