Insertion of SnCl2 into the Pd–Cl bond: mechanistic elucidation and antitumor evaluation of trichlorostannyl palladium–NHC allyl complexes in ovarian cancer models

Abstract

The development of effective and selective metal-based chemotherapeutics remains a central challenge in ovarian cancer treatment, particularly in addressing resistance to platinum agents. Herein, we report the design, synthesis, and biological evaluation of a novel series of heterobimetallic Pd(II)/Sn(II) η³-allyl complexes bearing N-heterocyclic carbene (NHC) ligands. Thirteen complexes were efficiently prepared via SnCl₂ insertion into the Pd–Cl bond of allyl–palladium precursors, and fully characterized by NMR, IR, and X-ray diffraction. DFT calculations revealed a stepwise reaction mechanism initiated by a favourable Sn⋯Cl interaction, followed by insertion into the Pd–Cl bond. All compounds exhibited pronounced cytotoxicity across cisplatin-sensitive, cisplatin-resistant, and high-grade serous ovarian cancer (HGSOC) cell lines, with selected derivatives, particularly 2i and 2k, showing remarkable tumour selectivity. Lead compound 2i retained potent activity in patient-derived tumour organoids (PDTOs), including a platinum-resistant model, while remaining inactive in a non-malignant fallopian tube epithelium organoid, highlighting its favourable therapeutic window. Mechanistic studies indicate that 2i primarily targets thioredoxin reductase (TrxR) and mitochondria, as evidenced by early cytochrome c release and loss of mitochondrial membrane potential, with subsequent DNA damage occurring downstream, consistent with a mitochondria-driven apoptotic pathway distinct from classical platinum drugs. These findings position Pd(II)/Sn(II) η³-allyl complexes, and 2i in particular, as promising candidates for metal-based anticancer therapy.