Lipophilicity-dependent ruthenium N-heterocyclic carbene complexes as potential anticancer agents

Abstract

Five Ru(II)-N-heterocyclic carbenes (NHC) (1-5) were synthesized by reacting the appropriately substituted imidazolium chlorides with Ag2O, forming the NHC-silver chloride in situ followed by transmetalation with dimeric p-cymene ruthenium(II) dichloride. All the complexes were characterized by NMR and ESI-MS, and complex 1 was also characterized by single-crystal X-ray diffraction. The IC50 values of these five complexes were determined by the MTT-based assay on four human cancer cell lines, SKOV-3 (ovarian), PC-3 (prostate), MDA-MB-231 (breast) and EC109 (esophagus). The cytotoxicities of these complexes changed from a moderate effect to a fine one, corresponding to the increasing lipophilicity order of the complex of 2 < 1 < 3 < 4 < 5 (0.91, 0.88, 1.36, 1.85 and 2.62 for 1–5 respectively). Complex 5 showed the most cytotoxicity with the IC50 values 10.3 ± 0.3 μM for SKOV-3, 2.9 ± 0.1 μM for PC-3, 8.2 ± 0.6 μM for MDA-MB-231, 6.4 ± 0.2 μM for EC109 cell lines. Due to the superior cytotoxicity of complex 5 against the PC-3 cell lines, further biological evaluations were carried out to elucidate its action mechanism. The morphologic changes and cell cycle analysis showed that complex 5 can inhibit PC-3 cell lines by inducing cell cycle arrest at the G2/M phase. The DNA binding experiments further demonstrate that complex 5 has a better binding ability for DNA (Kb = 2.2 × 10(6) M(-1)) than complexes 1-4 (3.8 × 10(5), 7.0 × 10(5), 5.7 × 10(5), and 1.9 × 10(5) respectively).

N‐Heterocyclic Carbene (NHC)‐Stabilized Ru0 Nanoparticles: In Situ Generation of an Efficient Transfer Hydrogenation Catalyst

“…The untethered ruthenium NHC complexes weres ynthesized by transferring the NHC from AgNHC generated in situ [38,39] from the NHC precursor (L) and silver oxide [38] in the dark to Ru in the dimer of dichloro(p-cymene)ruthenium(II) [40,41] (Scheme 1).…”

Synthesis, Structure, Biological Evaluation, and Catalysis of Two Pyrazole‐Functionalized NHC–RuII Complexes

“…Moreover, the cells exhibited shrinkage and became round. This indicated that complex 3a can induce apoptosis of the cancer cells . Finally, scratch‐wound cell migration assays of LoVo cells were conducted (Figure ).…”

“…In contrast, complex 3b , bearing the same NHC–Ru–( p ‐cymene) core, was less efficacious than either complex 3a or cisplatin in all tested cancer cells. The enhanced cytotoxicity activity of complex 3a may be attributed to the high lipophilicity substitution of mesityl at the position of imidazolylidene ring promoting cellular uptake . Several other Ru–NHCs, including Grubbs catalysts, have been evaluated for their anticancer properties .…”

Chelating N-heterocyclic carbene–carboranes offer flexible ligand coordination to IrIII, RhIII and RuII: effect of ligand cyclometallation in catalytic transfer hydrogenation

“…The solid-state structures ( Figure 3) show piano stool geometry around the metal centres, with each metal bearing two chloride atoms, an NHC and either Cp* (2b) or p-cymene (6b). The M-Ccarbene bond lengths of 1.92(3) Å (2b) and 2.064(7) Å (6b) are relatively short when compared to other IrCp*(NHC)Cl2 and Ru(pcymene)(NHC)Cl2 complexes in the literature, 37,[41][42][43][44][45] which may be an effect of the carborane substituent causing the carbenic carbon to be more nucleophilic than other NHCs. Similarly to complex 3a, the Ir complex 2b underwent cyclometallation upon reaction with Ag2O in MeCN.…”