Salophen-type Macrocyclic Schiff Base Ligand and its Metal Complexes: Exploring in vitro Anticancer Efficacy via in silico Topoisomerase IIꞵ Enzyme Targeting

Abstract

Cancer persists as a principal cause of global mortality. Despite significant progress in cancer therapeutics in recent decades, chemotherapy remains a primary modality for cancer treatment. Based on their mechanism of action, commonly used chemotherapeutic agents can be classified into several categories, including Topoisomerase inhibitors. Here, a newly synthesized Salophen-type macrocyclic Schiff base ligand (5E,19E)-3-bromo-12,13-dihydrodibenzo[e,m]pyrido[2,3-i][1,4]dioxa[8,11]diazacyclotetradecine (4) and its metal complexes (5a-5d) have been reported as potent anticancer agents exhibiting Topoisomerase IIβ inhibitory activity. In silico docking studies elucidated their binding interactions with the Topoisomerase IIβ enzyme (PDB ID: 4G0V) active site. The docking simulation results indicated that the ligand showed most favorable interaction, with a binding energy -10.3 kcal/mol. Also, in vitro anticancer studies using the MTT assay against the HepG2 liver cancer cell line corroborated these findings, demonstrating that the ligand exhibited the strongest inhibitory action with an IC50 of 0.09 µM, comparable to the standard anticancer drug Doxorubicin.