Copper and Manganese Complexes of Pyridinecarboxaldimine Induce Oxidative Cell Death in Cancer Cells

• Published in: ACS applied bio materials Vol. 7; no. 10; pp. 6696 - 6705
• Main Authors: Vechalapu, Sai Kumari, Kumar, Rakesh, Sachan, Sharad Kumar, Shaikh, Kanchan, Mahapatra, Amarjyoti Das, Draksharapu, Apparao, Allimuthu, Dharmaraja
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 21.10.2024
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biocompatible Materials - chemical synthesis; Biocompatible Materials - chemistry; Biocompatible Materials - pharmacology; Cell Death - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Copper - chemistry; Copper - pharmacology; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Manganese - chemistry; Manganese - pharmacology; Materials Testing; Molecular Structure; Oxidation-Reduction; Particle Size; Pyridines - chemistry; Pyridines - pharmacology; Reactive Oxygen Species - metabolism; Pyridine imine ligand; 3d-complexes; combination therapy; antiproliferative agents; oxidative stress
• ISSN: 2576-6422; 2576-6422
• DOI: 10.1021/acsabm.4c00854

Leveraging the versatile redox behavior of transition metal complexes with heterocyclic ligands offers significant potential for discovering new anticancer therapeutics. This study presents a systematic investigation of a pyridinecarboxaldimine ligand (PyIm) with late 3d-transition metals inhibiting cancer cell proliferation and the mechanism of action. Synthesis and thorough characterization of authentic metal complexes of redox-active late 3d-transition metals enabled the validation of antiproliferative activity in liver cancer cells. Notably, (PyIm)2Mn­(II) (1) and (PyIm)2Cu­(II) (5) complexes exhibited a good inhibitory profile against liver cancer cells (EC50: 4.0 μM for 1 and 1.7 μM for 5) with excellent selectivity over normal kidney cells (Selectivity index, SI = 17 for 5). Subsequently, evaluation of these complexes in cancers cell lines from four different sites of origin (liver, breast, blood, and bone) demonstrated a predominant selectivity to liver and a moderate selectivity to breast cancer and leukemia cells over the normal kidney cells. The mechanism of action studies highlighted no expected DNA damage in cells, rather, the enhancement of extracellular and intracellular reactive oxygen species (ROS) resulting in mitochondrial damage leading to oxidative cell death in cancer cells. Notably, these complexes potentiated the antiproliferative effect of commercially used cancer therapeutics (cisplatin, oxaliplatin, doxorubicin, and dasatinib) in liver cancer cells. These findings position redox-active metal complexes for further evaluation as promising candidates for developing anticancer therapeutics and combination therapies.