Palladium(II)-Indenyl Complexes Bearing N‑Heterocyclic Carbene (NHC) Ligands as Potent and Selective Metallodrugs toward High-Grade Serous Ovarian Cancer Models

In this study, we synthesized novel Pd(II)-indenyl complexes
using
various N-heterocyclic carbene (NHC) ligands, including
chelating NHC-picolyl, NHC-thioether, and diNHC ligands, and two monodentate
NHCs. Transmetalation reactions between a Pd(II)-indenyl precursor
and silver-NHC complexes were generally employed, except for chelating
diNHC derivatives, which required direct reaction with bisimidazolium
salts and potassium carbonate. Characterization included NMR, HRMS
analysis, and single-crystal X-ray diffraction. In vitro on five ovarian cancer cell lines showed notable cytotoxicity, with
IC50 values in the micro- and submicromolar range. Some
compounds exhibited intriguing selectivity for cancer cells due to
higher tumor cell uptake. Mechanistic studies revealed that monodentate
NHCs induced mitochondrial damage while chelating ligands caused DNA
damage. One chelating NHC-picolyl ligand showed promising cytotoxicity
and selectivity in high-grade serous ovarian cancer models, supporting
its consideration for preclinical study.