Expanding the scope of platinum-NHC complexes: trans-Pt(II) and Pt(0) architectures for ovarian cancer treatment

Ovarian cancer therapy relies heavily on platinum-based drugs, yet clinical efficacy is limited by toxicity and the rapid emergence of resistance. Herein, we report a systematic study of trans-configured Pt(II)-NHC and less conventional Pt(0)-NHC complexes as alternative platinum architectures for the treatment of ovarian cancer, including cisplatin-resistant disease. A sustainable and operationally simple synthetic platform enabled the preparation of a structurally coherent library of trans-[Pt(NHC)Cl₂(L)] and [Pt(NHC)(dvtms)] derivatives. In the Pt(II) series, L comprises dimethyl sulfide, pyridine, imidazole, benzimidazole, benzotriazole, 2-aminopyridine, 2-aminoquinoline, and phenazine, allowing systematic modulation of steric and electronic properties. The Pt(0) complexes incorporate dvtms (1,3-divinyltetramethyldisiloxane) as an olefin-stabilizing ligand. Both classical and backbone-functionalized N-heterocyclic carbenes (NHCs) were investigated, the latter accessed through recently developed mild one-pot methodologies, thereby enabling direct evaluation of backbone modification as a medicinal design element. Biological assessment in A2780 and A2780cis ovarian cancer cells reveals that many trans-Pt(II)-NHC complexes display cytotoxicity comparable to or exceeding that of cisplatin and, crucially, retain activity in the resistant model. Clear structure-activity relationships emerge: the nature of the NHC ligand predominates over variation of the neutral co-ligand. In addition, most of the newly synthesized Pt(0) complexes combine high antiproliferative activity with no detectable toxicity toward non-cancerous fibroblasts, highlighting an unprecedented in vitro selectivity within this family.