Metal NHC Complexes with Naphthalimide Ligands as DNA-Interacting Antiproliferative Agents

Naphthalimide-based N-heterocyclic carbene (NHC) complexes of the type [(1,5-cyclooctadiene)(NHC) RhCl)] (4a-c), [(p-cymene)( NHC) RuCl2)] (5a-c), and [(NHC) CuBr] (6a-c) were synthesized and investigated as antiproliferative agents that target DNA. The cytotoxic effects were largely driven by the naphthalimide structure, which is a DNA-intercalating moiety. Regarding the metal center, the highest activities were observed with the rhodium complexes, and cytotoxic activity was significantly lower for the ruthenium derivatives. The stable coordination of the NHC ligands of selected complexes 4b and 5b in solution was confirmed, and their DNA binding properties were studied by UV/Vis spectroscopy, mass spectrometry, and circular dichroism. Stable intercalative binding into the DNA for all selected naphthalimide-based complexes is indicated by high DNA binding constants. Particularly efficient binding was observed in the case of the rhodium complex 4b. More detailed biological studies on 4b showed promising activities against multidrug-resistant Nalm-6 cells and confirmed an important role for mitochondrial pathways in 4b-induced apoptosis.