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

Abstract

Naphthalimide-based N-heterocyclic carbene (NHC) complexes of the type [(1,5-cyclooctadiene)(NHC)RhCl)] (4 a-c), [(p-cymene)(NHC)RuCl )] (5 a-c), and [(NHC)CuBr] (6 a-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 4 b and 5 b 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 4 b. More detailed biological studies on 4 b showed promising activities against multidrug-resistant Nalm-6 cells and confirmed an important role for mitochondrial pathways in 4 b-induced apoptosis.

Synthesis and Biological Evaluation of Organometallic Complexes Bearing Bis‐1,8‐naphthalimide Ligands

“…The growth of Gram‐negative bacteria and C. albicans was not substantially affected. This effect corresponds with the previous observations, where naphthalimide‐based metal NHC complexes selectively inhibited the replication of the Gram‐positive strains causing at the same time no major damage to the Gram‐negative strains (Table ).…”

“…The compounds triggered strong antiproliferative effects in cancer cells as well as in bacteria, which were in most cases driven by the activity of the 1,8‐naphthalimide moiety. Importantly, for rhodium(I) and ruthenium(II) NHC derivatives we could confirm additional coordinative binding beyond the 1,8‐naphthalimide related largely intercalative binding mode …”

“…We have recently reported on organometallics containing NHC ligands based on 1,8‐naphthalimides , . These conjugates feature the combination of DNA interacting naphthalimides with a metal based mechanism of drug action (see Figure ).…”

Pyrimidine Derivatives with Terminal Pyridyl Heterocycles: Facile Synthesis and Their Antiproliferative Activities

“…This implies that 2 and 3 do not show any selectivity for the carcinoma cells in the same doses/concentration range. Nevertheless, the cytotoxicity of these pyridine/pyrimidine‐based molecules against these carcinoma cell lines is superior in comparison with several organic ligands as well as their metal complexes such as N‐heterocyclic carbenes and their organometallic Au(I) , Ru(II), Rh(I), and Cu(I) N‐heterocyclic carbenes complexes.…”

On the binding modes of metal NHC complexes with DNA secondary structures: implications for therapy and imaging

“…61 Building on a similar approach, 59 NHC-based complexes exhibiting such a dual binding mode were prepared with ruthenium(II) (18) and rhodium(I) (19) ions (Figure 6). 67 Regarding the antiproliferative effects, the rhodium-based compound exhibited low micromolar activities in the breast carcinoma (MCF-7) and colon carcinoma (HT-29) cell lines, while the ruthenium congener (18) …”