Mechanistic Insights into Chloride-Dependent Uncaging Reaction of Propargyl and Allene-Protected Substrates by Pd-Complexes.

This study investigates the effect of chloride levels on the mode of action of palladium complexes for the activation of propargyl- and allene-protected fluorophores and chemotherapeutic drugs through uncaging reactions. Four Pd(II) complexes were synthesized and characterized using various spectroscopic techniques to confirm their structure and electronic properties. Kinetic studies and density functional theory calculations revealed that chloride ions in phosphate buffered saline (PBS) significantly enhance catalytic efficiency, particularly for allenyl-protected substrates compared to propargylic counterparts. This enhancement is attributed to the neutral charge nature of the Pd complex. The data suggest that neutral complexes are less prone to chloride exchange by water molecules. Additionally, chloride ligands counterbalance the unusually high stability of the key σ-bound η-Pd intermediates in the aquo complexes in PB, leading to an overall higher reactivity. These results highlight the impact of fine-tuning the electronic properties of the metal center through both designed ligands and environmental factors. Bench evaluations and tests with living breast cancer cells demonstrated that a Pd catalyst complex with a bidentate ligand effectively activates the prodrugs propargyl-5-fluorouracil (Prop-5FU) and allene-5-Fluorouracil (Alle-5FU), the latter being a novel prodrug. The Pd catalyst successfully released the active drug, inducing significant cytotoxicity, especially with Alle-5FU, which operates at lower catalyst concentrations than Pro-5FU.