Chemical Stabilization and Transformation of Schiff Base Scaffold: A Path toward Superior Platinum-Based Anti-Cancer Stem Cell Drugs

Abstract

The clinical application of platinum-based anticancer agents is limited by poor aqueous stability, low solubility, and dose-limiting toxicities. Here, we report two Pt(II) complexes based on a Schiff base ligand and its reduced imine derivative, designed to overcome these limitations. We show that ligand stabilization through imine reduction markedly improves solution stability, which emerges as an important contributor to interaction, cellular responses, and antiproliferative activity. ICP-MS analysis demonstrated efficient intracellular platinum accumulation with preferential nuclear localization. The lead compound also displayed potent activity against gastric cancer stem-like cells by impairing self-renewal and pluripotency. Transcriptomic and functional analyses associated this effect with suppression of stemness and epithelial-to-mesenchymal transition-related transcriptional programs, reduced OCT3/4 expression, and activation of DNA damage, apoptosis, and oxidative stress pathways. These findings identify a promising Pt(II) scaffold for targeting cancer stem cell-associated phenotypes and establish ligand stabilization as an effective strategy for developing next-generation platinum anticancer agents.