Anthracenyl Functionalization of Half-Sandwich Carbene Complexes: In Vitro Anticancer Activity and Reactions with Biomolecules

Abstract

N-Heterocyclic carbene (NHC) ligands are widely investigated in medicinal inorganic chemistry. Here, we report the preparation and characterization of a series of half-sandwich [M­(L)­(NHC)­Cl2] (M = Ru, Os, Rh, Ir; L = cym/Cp*) complexes with a N-flanking anthracenyl moiety attached to imidazole- and benzimidazole-derived NHC ligands. The anticancer activity of the complexes was investigated in cell culture studies where, in comparison to a Rh derivative with an all-carbon-donor-atom-based ligand (5a), they were found to be cytotoxic with IC50 values in the low micromolar range. The Ru derivative 1a was chosen as a representative for stability studies as well as for biomolecule interaction experiments. It underwent partial chlorido/aqua ligand exchange in DMSO-d 6/D2O to rapidly form an equilibrium in aqueous media. The reactions of 1a with biomolecules proceeded quickly and resulted in the formation of adducts with amino acids, DNA, and protein. Hen egg white lysozyme crystals were soaked with 1a, and the crystallographic analysis revealed an interaction with an l-aspartic acid residue (Asp119), resulting in the cleavage of the p-cymene ligand but the retention of the NHC moiety. Cell morphology studies for the Rh analog 3a suggested that the cytotoxicity is exerted via mechanisms different from that of cisplatin.

Synthetic Strategy Towards Heterodimetallic Half-Sandwich Complexes Based on a Symmetric Ditopic Ligand

“…In the case of the Os-Ir compound 2f , minor changes were observed, but these were not as pronounced as those observed for 2c ( Supplementary Figure S22 ). Interestingly, for the Cp* signals in the spectra of both compounds, we observed changes in the aliphatic region which require further investigations ( Banerjee et al, 2018 ; Lee B. Y. T. et al, 2021 ; Lee B. et al, 2021 ). In 10% DMSO- d 6 /D 2 O, the spectra of 2f changed over time which was suppressed by the addition of 100 mM NaCl, to approximate the standard chloride concentration in blood.…”

Triazolyl- vs Pyridyl-Functionalized N-Heterocyclic Carbene Complexes: Impact of the Pendant N-Donor Ligand on Intramolecular C–C Bond Formation

“…Other metals from the platinum metal family, in particular, Ir, Os, Rh, and Ru, are employed in the design of novel metal–NHC compounds. We have recently reported a series of [M­(L)­(NHC)­Cl 2 ] complexes (where M = Ru, Os, Rh, Ir; L = η 6 - p -cymene [cym], η 5 -pentamethylcyclopentadienyl [Cp*]) with an N -flanking anthracenyl moiety attached to the NHC ligands, and the complexes showed excellent cytotoxic activity . We have shown that the anthracenyl-functionalized NHC–Ru II (cym) complex forms adducts with hen egg white lysozyme by binding to an Asp residue and a π-stacking interaction with a Trp residue .…”

“…We have recently reported a series of [M­(L)­(NHC)­Cl 2 ] complexes (where M = Ru, Os, Rh, Ir; L = η 6 - p -cymene [cym], η 5 -pentamethylcyclopentadienyl [Cp*]) with an N -flanking anthracenyl moiety attached to the NHC ligands, and the complexes showed excellent cytotoxic activity . We have shown that the anthracenyl-functionalized NHC–Ru II (cym) complex forms adducts with hen egg white lysozyme by binding to an Asp residue and a π-stacking interaction with a Trp residue . Interestingly, we showed that [Rh­(Cp*)­(NHC-anthracenyl)­Cl 2 ] A can undergo intramolecular C–C coupling, forming complex B (Figure ) with a seemingly nonadentate all-carbon donor atom ligand. , This involves the activation of the Cp* ligand for reactions at the methyl groups, − which also led to intramolecular cross-coupling reactions in Rh­(Cp*)­(NHC) complexes with an N -methylpyridinium- and pentafluorobenzyl-functionalized NHC ligand .…”

“…We have shown that the anthracenyl-functionalized NHC–Ru II (cym) complex forms adducts with hen egg white lysozyme by binding to an Asp residue and a π-stacking interaction with a Trp residue . Interestingly, we showed that [Rh­(Cp*)­(NHC-anthracenyl)­Cl 2 ] A can undergo intramolecular C–C coupling, forming complex B (Figure ) with a seemingly nonadentate all-carbon donor atom ligand. , This involves the activation of the Cp* ligand for reactions at the methyl groups, − which also led to intramolecular cross-coupling reactions in Rh­(Cp*)­(NHC) complexes with an N -methylpyridinium- and pentafluorobenzyl-functionalized NHC ligand . To alter the properties of such compounds, we introduce here pyridyl or triazolyl functional groups to the anthracenyl-NHC ligand system, converting them into bidentate ligand systems with coordination via a C , N -donor system.…”

Half-Sandwich Cyclometalated RhIII Complexes Bearing Thiolate Ligands: Biomolecular Interactions and In Vitro and In Vivo Evaluations

“…Among the existing anticancer remedies with metal atoms, Pt-containing compounds (for instance carboplatin, oxaliplatin, and cisplatin) are the most effective and frequently used drugs with long-lasting therapeutic success in the treatment of cancer patients. − However, chemotherapy with the Pt-based drugs suffers from many limitations, serious side effects, and, in some cases, lack of selectivity . These barriers and drawbacks have engaged the cancer research field to use other transition metals such as gold, ruthenium, iridium, rhodium, and palladium . Some of these metal complexes, auranofin (Au complex), BOLD-100, and TLD1433 (Ru complexes), progressed to clinical trials and provided an appropriate alternatives for Pt antiproliferative agents.…”