Palladium Complexes with Tridentate N‑Heterocyclic Carbene Ligands: Selective “Normal” and “Abnormal” Bindings and Their Anticancer Activities

A series of new imidazolium salts was synthesized by simple quaternization reactions of 1-benzyl-1<i>H</i>-imidazole or 1-benzyl-2-methyl-1<i>H</i>-imidazole and their derivatives with 2-chloro-<i>N</i>-(pyridin-2-ylmethyl)­acetamide. These resulting imidazolium salts were successfully employed as ligand precursors for the syntheses of novel palladium­(II) complexes bearing tridentate ligands of N-heterocyclic carbene, amidate, and pyridine donor moieties. Simple tuning of the reaction conditions allowed selective coordination of the N-heterocyclic carbene moiety in either “normal” or “abnormal” binding modes. An isomeric pair of palladium complexes with “normal” and “abnormal” N-heterocyclic carbenes was successfully characterized by single-crystal X-ray diffraction studies. Theoretical calculations indicated that the palladium complex with “normal” NHC coordination was more thermally stable than its isomeric complex with “abnormal” NHC binding. The potential of these two sets of palladium complexes as anticancer drugs was evaluated, and the results showed that some of these novel complexes exhibited promising inhibition activity against human ovarian cancer cell lines. The inhibition activity of these novel complexes was highly structurally dependent. While the nNHC complex bearing an <i>N</i>-3-methoxybenzyl group appeared to be the most active compound, its isomeric aNHC complex did not exhibit any inhibition activity toward TOV21G cells. In contrast, in the case of an isomeric pair of palladium complexes bearing <i>N</i>-4-fluorobenzyl groups, the aNHC complex showed activity superior to that of the nNHC complex.