Triazolyl‐Functionalized N‐Heterocyclic Carbene Half‐Sandwich Compounds: Coordination Mode, Reactivity and in vitro Anticancer Activity

Abstract

We report investigations on the anticancer activity of organometallic [M II/III (η 6 -p-cymene/η 5 -pentamethylcyclopentadienyl)] (M = Ru, Os, Rh, and Ir) complexes of N-heterocyclic carbenes (NHCs) substituted with a triazolyl moiety. Depending on the precursors, the NHC ligands displayed either mono-or bidentate coordination via the NHC carbon atom or as N,Cdonors. The metal complexes were investigated for their stability in aqueous solution, with the interpretation supported by density functional theory calculations, and reactivity to biomolecules. In vitro cytotoxicity studies suggested that the nature of both the metal center and the lipophilicity of the ligand determine the biological properties of this class of compounds. The Ir III complex 5 d bearing a benzimidazolederived ligand was the most cytotoxic with an IC 50 value of 10 μM against NCI-H460 non-small cell lung carcinoma cells. Cell uptake and distribution studies using X-ray fluorescence microscopy revealed localization of 5 d in the cytoplasm of cancer cells.

Impact of Coordination Mode and Ferrocene Functionalization on the Anticancer Activity of N-Heterocyclic Carbene Half-Sandwich Complexes

“…The in vitro anticancer activity of the pro-NHCs a – c and their complexes 1a–4a , 1c – 4c , 1b , 3b , and 4b was studied against human colorectal (HCT116), non-small-cell lung (NCI-H460), cervical carcinoma (SiHa), and colon adenocarcinoma (SW480) cells. Compound a exhibited similar cytotoxicity as its non-ferrocenyl-functionalized derivative . In contrast, the ferrocene-containing pyridyl-pendant derivative b was more cytotoxic than the benzyl-substituted c as well as a .…”

“…In contrast, the ferrocene-containing pyridyl-pendant derivative b was more cytotoxic than the benzyl-substituted c as well as a . Coordination of a to metal centers afforded hetero-dinuclear complexes that were significantly more active than the other compounds of the series (Table ), including their benzyl-substituted analogues . The Rh and Ir derivatives 3a and 4a showed IC 50 values in the low micromolar range (2–9 μM), in a range similar to the anticancer drug cisplatin, while the Os derivative 2a was less active, with IC 50 values ranging from 12 to 15 μM.…”

“…Coordination of a to metal centers afforded hetero-dinuclear complexes that were significantly more active than the other compounds of the series (Table 2), including their benzylsubstituted analogues. 26 The Rh and Ir derivatives 3a and 4a showed IC 50 values in the low micromolar range (2−9 μM), in a range similar to the anticancer drug cisplatin, while the Os derivative 2a was less active, with IC 50 values ranging from 12 to 15 μM. Coordination of a to a Ru(cym) moiety afforded 1a, which showed only a moderate enhancement of the activity against SiHa and SW480 cells.…”

“…We have previously reported a series of cationic [M II/III (cym/Cp*)] complexes featuring a C,N-coordinating NHC ligand functionalized with a benzyl-triazolyl moiety . The Ir­(Cp*) derivative exhibited low to moderate antiproliferative activity and the ability to accumulate in the cytoplasm of cancer cells.…”

Current status of iridium-based complexes against lung cancer

“…Compound 67 (Figure 5) has good inhibitory activity against A549 lung cancer cells (Table 2), and it also shows nanomolar antimalarial activity, which is superior to chloroquine and artemisinin. Subsequently, a half sandwich Ir(III) compound 68 (Figure 5) with triazolyl substituted N-heterocyclic carbene as ligand was reported, which has good antitumor activity against NCI-H460 lung cancer cells (Table 2) (Tong et al, 2021). In the same year, Shao et al developed four triphenylamine-modified fluorescent halfsandwich iridium (III) thiosemicarbazone (TSC) compounds, which exhibited fluorescence properties under 405 nm light (Shao et al, 2021).…”