Design of nickel chelates of tetradentate N-heterocyclic carbenes with subdued cytotoxicity

A series of nickel complexes, 1b–3b, exhibiting subdued cytotoxicity have been designed with the intent of their use as agents for developing resistance to nickel toxicity. Indeed, the nickel complexes, 1b–3b, display less cytotoxic activity towards two commonly occurring human cancer cell lines namely, HeLa cells (16–64%) and MCF-7 cells (70–90%) in culture as compared to the maximum inhibition by NiCl2 · 6H2O under analogous conditions at three different concentrations (1 μM, 5 μM and 20 μM). Similarly, the suppression of cytotoxicity through chelation of the metal ion can also be seen in normal cells as was evident from a significant reduction in cytotoxicity (9–41%) for a non-tumorigenic CHO cell line in case of a representative complex 3b. The reduction in carcinogenic activity in the complexes relative to nickel(II) ion from NiCl2 · 6H2O is brought about by successful chelation of the metal center by a class of specially designed new tetradentate N/O-functionalized N-heterocyclic carbene ligands. The two strongly σ-donating carbene moieties coupled with two negatively charged amido moieties present in the N-heterocyclic carbene ligands facilitate complete chelation of the metal center and thereby significantly reduce the cytotoxic effects of the metal.