Synthesis, characterization, molecular docking, and cytotoxicity study of ruthenium (II/III) polypyridyl complexes

A new polypyridyl ligand 4-(4-nitrophenoxy)-N,N-bis (pyridin-2-ylmethyl)aniline (<bold>L1</bold>) and its three ruthenium (II/III) complexes, [Ru (Cl)(3)L1] (<bold>C1</bold>), [Ru(L1)(2)]Cl (<bold>C2</bold>), and [RuCl (dpa)L1] (<bold>C3</bold>) where dpa = 2,2-dipyridylamine, have been successfully synthesized and characterized using Fourier-transform infrared spectroscopy (FTIR), elemental analysis, proton nuclear magnetic resonance (H-1 NMR), high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), thermal analysis (thermogravimetric analysis [TGA] and differential scanning calorimetry [DSC]), UV/Vis absorption, and magnetic susceptibility. The structures of the ligand and the complexes were optimized, and the structural characteristics were determined by density functional theory (DFT) using the B3LYP-GD3/6-311G++(d,p) method. Optimized FTIR vibrational frequencies and H-1 NMR chemical shifts agreed well with the corresponding experimental FTIR and H-1 NMR data. In vitro cytotoxicity of the ligand and the complexes were evaluated against the MCF-7 breast cancer cell line. Ligand <bold>L1</bold> was the most potent with an IC50 of 38.45 mu M, followed by <bold>C2</bold> with an IC50 of 45.23 mu M. However, the ligand and the complexes showed low antiproliferative activity compared to cisplatin, which had an IC50 of 9.67 mu M. To predict the reactivity trend of <bold>L1</bold> and the complexes, frontier molecular orbital (FMO) analysis was performed. The FMO energy gap (Eg = E-LUMO - E-HOMO) for <bold>C2</bold> was found to be 1.675 eV, which was the lowest among all the complexes or <bold>L1</bold>. In addition, molecular docking studies were carried out so as to predict the binding capacity of <bold>L1</bold> and the complexes to estrogen receptor alpha (ER-alpha). The results showed that <bold>C2</bold> has the most negative binding energy score (-9.63 kcal/mol), which indicates more stable adducts with the key amino acid residues at the active sites of ER-alpha. Furthermore, <bold>C2</bold> displayed the lowest inhibition constant (K-i) of 0.09 mu M compared to all the complexes or <bold>L1</bold>. These results are very promising and show that the novel complex <bold>C2</bold> may help in the development of anticancer drugs.