Water soluble Ru(ii)–arene complexes of the antidiabetic drug metformin: DNA and protein binding, molecular docking, cytotoxicity and apoptosis-inducing activity

Abstract

Two water soluble Ru(II)–arene complexes of the type [Ru(η⁶-arene)(met)Cl]Cl 1 and 2, where the arene is either p-cymene (1) or benzene (2) and met is metformin (antidiabetic drug) have been isolated and characterized by analytical and spectral methods. The X-ray crystal structure of 1 reveals that the coordination geometry around Ru(II) is described as the familiar pseudo-octahedral “piano-stool” structure. Absorption and emission spectral studies reveal that the complexes interact with calf thymus DNA through hydrophobic and hydrogen bonding interactions of coordinated ligands with the DNA base pairs. Molecular docking studies show that complex 1 effectively docks in the major groove of DNA. The decrease in viscosities of CT DNA upon binding to 1 and 2 suggest the covalent mode of DNA binding of complexes. Further, the covalent mode of binding is validated by the retardation of the mobility of supercoiled (SC) plasmid DNA by the formation of covalent adducts observed in gel electrophoretic mobility studies. The protein binding affinity of the complexes depends upon the arene ligand and follows the order of p-cymene (1) > benzene (2), which is the same as that for DNA binding affinity. Docking studies with BSA and transferrin show that the complex–protein interaction is stabilized by hydrophobic as well as hydrogen bonding interactions. The α-amylase inhibition assay of 1 and 2 indicates that they have the potency to exhibit the antidiabetic activity in vitro. A study of cytotoxicity of 1 and 2 against human breast carcinoma (MDA-MB-231), human lung carcinoma (A549), human ovarian carcinoma (A2780) cell lines and non-tumorigenic human embryonic kidney (HEK293) cells reveals that they are specifically toxic to cancerous cells and non-toxic to normal cells. Remarkably, complexes 1 and 2 exhibit cytotoxicity with potency more than the metformin suggesting that the incorporation of antidiabetic drug with the organometallic Ru-arene frameworks is potential approach to develop effective anticancer drugs. The morphological changes observed by employing AO/EB and Hoechst 33258 staining methods reveal that the complexes 1 and 2 induce an apoptotic mode of cell death in breast cancer cells.