The Non-Steroidal Anti-Inflammatory Drugs Based on Zinc(II) Picoline Complexes: Synthesis, Characterization, and Evaluation of Antiproliferative Effects Against Human Breast Adenocarcinoma MDA-MB Cells by Inducing ROS-Mediated Apoptosis and Down-Regulating PI3K/Akt Signaling Pathway

Abstract

This work aims to synthesize zinc(II) non-steroidal anti-inflammatory complexes and to evaluate their anticancer abilities on different cancer cell lines. In this context, four new zinc(II) complexes including the NSAIDs mefenamic acid or niflumic acid and picoline derivatives {[Zn 2 (1-mef) 3 (3-pic) 2 ] 1 , [Zn 3 (1-mef) 6 (2-pic) 2 ] 2 , [Zn 3 (1- mef) 6 (4-pic) 2 ] 3 and [Zn(nif) 2 (4-pic) 2 ]} 4 were synthesized. The molecular structures were identified by elemental analysis, FT -IR, 1 H NMR (complexes 2 and 3 ), UV-Vis, thermal analysis, and X-ray diffraction (complexes 1 and 4 ), indicating that one complex was mononuclear, one complex was binuclear, and two complexes were trinuclear. The deprotonated mefenamato ligands bind to the zinc(II) ion via carboxylate oxygen atoms and chelate in a bridging bidentate asymmetric form. The deprotonated niflumato ligand acts as a monodentate ligand. UV-Vis spectroscopy was used to assess the complexes' stability. The stoichiometry of the synthesized complexes was determined by 1 H NMR and thermal studies. XTT assays showed that all complexes exhibited dose-dependent antiproliferative effects against breast cancer MCF-7 and MDA-MB-453 cells, colon cancer HT-29 cells, and lung cancer A549 cells. The highest cytotoxicity was exhibited by complex 3 against MDA-MB-453 cells with an IC 50 value of 8.28 mu M. The mechanistic studies performed by flow cytometry revealed that complex 3 exerted its in vitro anticancer activity against MDA-MB-43 cells by inducing apoptosis, increasing ROS production, and inhibiting the PI3K/AKT signaling pathway.