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

Abstract

The substitution of phenyl rings in established drugs with ferrocenyl moieties has been reported to yield compounds with improved biological activity and alternative modes of action, often involving the formation of reactive oxygen species (ROS). Translating this concept to N-heterocyclic carbene (NHC) complexes, we report here organometallics with a piano-stool structure that feature di- or tridentate ligand systems. The ligands impacted the cytotoxic activity of the NHC complexes, but the coordination modes seemed to have a limited influence, which may be related to the propensity of forming the same species in solution. In general, the stability of the complexes in an aqueous environment and their reactivity to selected biomolecules were largely dominated by the nature of the metal center. While the complexes promoted the formation of ROS, the levels did not correlate with their cytotoxic activity. However, the introduction of ferrocenyl moieties had a significant impact on the antiproliferative potency of the complexes and, in particular, some of the ferrocenyl-functionalized compounds yielded IC50 values in the low μM range.

Exploring the phototoxicity of GSH-resistant 2-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)quinoline-based Ir(iii)-PTA complexes in MDA-MB-231 cancer cells

“…S10 ‡). [39][40][41] GSH plays an important role in the biological environment as: (i) GSH and its oxidized form GSSG endure the cellular redox homeostasis; (ii) the level of GSH is extremely preeminent in cancer cells to battle with ROS; 42 (iii) GSH forms a covalent adduct with cisplatin congeners or metallodrugs having a labile ligand, resulting in the deactivation of the complexes and enabling their efflux from cells. 42 Thus, kinetically inert metallodrugs are extremely needed, as they will not be prone to covalent adducts with GSH, and hence, we performed the stability study of these complexes in 1 mM aqueous GSH in the presence of 4 mM and 120 mM NaCl up to 48 h and monitored using a UVvisible spectrophotometer, NMR instrument and ESI-HRMS instrument.…”

Cationic N,S-chelate half-sandwich iridium complexes: synthesis, characterization, anticancer and antiplasmodial activity

“…These unsatisfactory outcomes of treatment have encouraged researchers to develop non-platinum anticancer complexes, including gold, osmium, iridium, rhodium, and ruthenium complexes, which may be able to exhibit better selectivity, diminish severe side effects, broaden the spectrum of sensitive tumors, and overcome platinum resistance. 30–38…”

“…These unsatisfactory outcomes of treatment have encouraged researchers to develop non-platinum anticancer complexes, including gold, osmium, iridium, rhodium, and ruthenium complexes, which may be able to exhibit better selectivity, diminish severe side effects, broaden the spectrum of sensitive tumors, and overcome platinum resistance. [30][31][32][33][34][35][36][37][38] Iridium-based drugs have been widely investigated in this area, and the results indicated their great potential as alternative anticancer agents, which not only exhibited high potency toward a wide range of cancer cells but also showed novel modes of action compared with the clinically used platinumbased drugs. Sadler and Liu groups prepared a series of Cp*Ir complexes based on N,N-, N,O-, O,O-and N,P-chelating ligands, which showed good anticancer activity against A2780, A549 and HeLa cells.…”

Increasing Anticancer Activity with Phosphine Ligation in Zwitterionic Half-Sandwich Iridium(III), Rhodium(III), and Ruthenium(II) Complexes

“…According to the structure type, these platinum group metal-based anticancer complexes can be divided into two main groups: cyclometalated complexes and half-sandwich complexes (Scheme ). Over the past few years, cyclometalated complexes have been gaining popular attention due to their excellent luminescence nature and pretty good cytotoxic efficacy under light, which afforded quite a wide range of applications for photodynamic therapy (PDT), molecular imaging, and bioprobes. , Recently, half-sandwich iridium­(III), rhodium­(III), ruthenium­(II), and osmium­(II) organometallic anticancer complexes with the structure type [(η 6 -arene)/(η 5 -Cp*)­M­(XY)­Cl] 0/+ (Cp*: C 5 (CH 3 ) 5 ; M: Ir, Rh, Ru, Os; XY: bidentate chelating ligands) have attracted widespread attention due to their amenable coordination structure and different mechanisms of action (MoAs) with platinum drugs. − Most of these studies concentrated on the preparation and application of neutral and cationic anticancer complexes with various bidentate XY ligands. − For example, the Sadler group has shown that switching on the cytotoxic potency of the corresponding iridium­(III) complexes could be realized by replacing neutral N , N -chelating ligand (2,2′-bipyridine) with the negatively charged anionic C , N -chelating ligand (2-phenylpyridine) (Scheme , I and II ). ,− Our group have also systematically investigated the counteranion effect on the cytotoxicity and biological activity of the cationic half-sandwich iridium­(III) complexes (Scheme , III ) . The above-mentioned studies indicated that the charge of the metal center, the substitution model of the chelate ligands, and the counteranion have a great influence on chemical reactivity and anticancer activity of the complexes.…”