Novel and Versatile Imine-N-Heterocyclic Carbene Half-Sandwich Iridium(III) Complexes as Lysosome-Targeted Anticancer Agents

Abstract

We, herein, report the synthesis, characterization, luminescence properties, anticancer, and antibacterial activities of a family of novel half-sandwich iridium(III) complexes of the general formula [(η-Cp)Ir(C^N)Cl]PF [Cp = pentamethylcyclopentadienyl (Cp*) or tetramethyl(biphenyl)-cyclopentadienyl (Cp)] bearing versatile imine-N-heterocyclic carbene ligands. In this complex framework, substituents on four positions could be modulated, which distinguishes this class of complex and provides a large amount of flexibility and opportunity to tune the cytotoxicity of complexes. The X-ray crystal structures of complexes 4 and 10 exhibit the expected "piano-stool" geometry. With the exception of 1, 2, and 11, each complex shows potent cytotoxicity, with IC (half-maximum inhibitory concentration) values ranging from 1.99 to 25.86 μM toward A549 human lung cancer cells. First, the effect of four positions bearing different substituents in the complex framework on the anticancer activity, that is, structure-activity relationship, was systematically studied. Complex 8 (IC = 1.99 μM) displays the highest anticancer activities, whose cytotoxicity is more than 10-fold higher than that of the clinical platinum drug cisplatin against A549 cancer cells. Second, their chemical reactivity including nucleobases binding, catalytic activity in converting coenzyme NADH to NAD, reaction with glutathione (GSH), and bovine serum albumin (BSA) binding is investigated. No reaction with nucleobase is observed. However, these iridium(III) complexes bind rapidly to GSH and can catalyze oxidation of NADH to NAD. In addition, they show moderate binding affinity to BSA and the fluorescence quenching of BSA by the iridium (III) complexes is due to the static quenching. Third, the mode of cell death was also explored through flow cytometry experiments, including cell cycle, apoptosis induction, reactive oxygen species (ROS) and mitochondrial membrane potential. It seems that cell cycle perturbation, apoptosis induction, increase of ROS level and loss of mitochondrial membrane potential together contribute to the anticancer potency of these complexes. Last, the use of confocal microscopy provides insights into the microscopic mechanism that the typical and most active complex 8 enters A549 lung cancer cells mainly through energy-dependent pathway and is located in lysosome. Furthermore, lysosome damage and nuclear morphology were detected by confocal microscopy. Nuclear condensation and apoptotic bodies may finally induce cells apoptosis. Interestingly, complex 8 also shows antibacterial activity against Gram-positive Staphylococcus aureus. This work may provide an alternative and effective strategy to smart design of potent organometallic half-sandwich iridium(III) anticancer drugs.

Organometallic Iridium Arene Compounds: The Effects ofC-Donor Ligands on Anticancer Activity

“…Of the class of C,C-donors, Han et al have reported functionalized phenyl NHC complexes which are all cytotoxic with complex 32 exhibiting high activity towards human lung carcinoma A549, which are 35-fold more cytotoxic than CDDP. 115 On analysis of the cell cycle, the complexes exhibit a disturbance in the sub-G1 or S phase, suggesting that these complexes have an effect on the growth cycle progression and can cause apoptosis, whilst inducing ROS. The subcellular localization in A549 cells was determined by confocal microscopy, and highlights an energy dependent mechanism of uptake.…”

Experimental and theoretical investigation of cyclometalated phenylpyridine iridium(iii) complex based on flavonol and ibuprofen ligands as potent antioxidant

“…[10][11][12][13][14] In particular, there have been several attempts to use Ir-based carbene compounds or complexes as antitumor agents; a series of half-sandwich Ir(III) complexes were synthesized or modeled and reported as potential anticancer drugs. [15][16][17][18][19][20] Indeed, one can expect for the new Ir(III) complexes, as well as for other metallodrugs, to (i) get stronger and more selective effects against tumors, (ii) extend the spectrum of cancer treatment and (iii) overcome the limits of Pt-based drugs such as the platin resistance and other severe side-effects.…”

Lysosome‐targeted potent half‐sandwich iridium(III) α‐diimine antitumor complexes

“…Organometallic transition metal‐based complexes exhibit a wide range of applications for the design of antitumor drugs due to their potential redox features, diverse structural types and varied ligand bonding modes . Organometallic complexes of the group VIIIB elements platinum, ruthenium, osmium, rhodium, palladium and iridium have received much attention as potential antitumor agents . Following the clinical success of platinum‐based antitumor drugs such as cisplatin, carboplatin and oxaliplatin, metal‐mediated antitumor drugs have attracted wide attention in chemotherapeutic research .…”