Seven novel half-sandwich Ir cyclopentadienyl complexes, [(η-Cp)Ir(N^N)Cl]PF, have been prepared and characterized, where Cp is Cp* or the biphenyl derivative Cp (CMeCHCH), and the N^N-chelating ligands are imino-pyridyl Schiff-bases. The X-ray crystal structures of complexes 2A, 2B, and 3A have been determined. Excitingly, most of the complexes show potent antiproliferative activity towards A549 and HeLa cancer cells, except for Cp* complex 1A towards HeLa cells. Cp complex 2B displayed the highest potency, about 19 and 6 times more active than the clinically used drug cisplatin toward A549 and HeLa cells, respectively. These complexes undergo hydrolysis, and the kinetics data have been calculated. DNA binding has been studied by interaction with nucleobases 9-ethylguanine and 9-methyladenine, cleavage of plasmid DNA, and interaction with ctDNA. Interaction with DNA does not appear to be the major mechanism of action. Protein binding (bovine serum albumin, BSA) has been established by UV-Vis, fluorescence and synchronous spectroscopic studies. The stability of complex 2B in the presence of GSH was evaluated. The complexes catalytically convert coenzyme NADH to NADvia hydride transfer. Cp complexes 2B and 4B induce cell apoptosis and arrest cell cycles at the S and G/M phases towards A549 cancer cells and increase the reactive oxygen species dramatically, which appear to contribute to the remarkable anticancer activity.

A series of half-sandwich Ir pentamethylcyclopentadienyl and Ru arene complexes containing P^P-chelating ligands of the type [(Cp/arene)M(P^P)Cl]PF, where M = Ir, Cp is pentamethylcyclopentadienyl (Cp*), or 1-biphenyl-2,3,4,5-tetramethyl cyclopentadienyl (Cp); M = Ru, arene is 3-phenylpropan-1-ol (bz-PA), 4-phenylbutan-1-ol (bz-BA), or p-cymene (p-cym), and P^P is 2,20-bis(diphenylphosphino)-1,10-binaphthyl (BINAP), have been synthesized and fully characterized, three of them by X-ray crystallography, and their potential as anticancer agents explored. All five complexes showed potent anticancer activity toward HeLa and A549 cancer cells. The introduction of a biphenyl substituent on the Cp* ring for the iridium complexes has no effect on the antiproliferative potency. Ruthenium complex [(η-p-cym)Ru(P^P)Cl]PF (5) displayed the highest potency, about 15 and 7.5 times more active than the clinically used cisplatin against A549 and HeLa cells, respectively. No binding to 9-MeA and 9-EtG nucleobases was observed. Although these types of complexes interact with ctDNA, DNA appears not to be the major target. Compared to iridium complex [(η-Cp*)Ir(P^P)Cl]PF (1), ruthenium complex (5) showed stronger ability to interfere with coenzyme NAD/NADH couple through transfer hydrogenation reactions and to induce ROS in cells, which is consistent with their anticancer activities. The redox properties of the complexes 1, 5, and ligand BINAP were evaluated by cyclic voltammetry. Complexes 1 and 5 arrest cell cycles at the S phase, Sub-G phase and G phase, respectively, and cause cell apoptosis toward A549 cells.

Chemotherapy is limited by its poor selectivity towards cancer cells over normal cells. Herein, we designed half-sandwich ruthenium imino-pyridyl complexes [(η-bz)Ru(N^N)Cl]PF to achieve selective cytotoxicity to cancer cells. This kind of ruthenium complex has unique characteristics and is worthy of further exploration in the design of new anticancer drugs.

Half-sandwich pseudo-octahedral pentamethylcyclopentadienyl Ir complexes of the type [(η-Cp)Ir(C^C)Cl]PF, where Cp is pentamethylcyclopentadienyl (Cp*), or its phenyl (Cp = CMeCH) or biphenyl (Cp = CMeCHCH) derivatives, and the C^C-chelating ligands are different N-heterocyclic carbene (NHC) ligands, have been synthesized and characterized. Three X-ray crystal structures have been determined. Except for Cp* complex 1A, the other eleven complexes 1B-4C all showed potent cytotoxicity, with IC values ranging from 2.9 to 46.3 μM toward HeLa human cervical cancer cells. The potency toward HeLa cells increased with additional phenyl substitution on Cp*: Cp > Cp > Cp*, and increased with the size of chain substitution on the C^C-ligand in the order: ph > butyl > ethyl > methyl. Complex [(η-CMeCHCH)Ir(L4)Cl]PF (4C) displayed the highest potency, and was about 3 times more active than the clinical platinum drug cisplatin. Complexes 1A-4C all undergo hydrolysis and their kinetics was studied. DNA binding appears not to be the major mechanism of action. The ability of these iridium complexes to catalyze hydride transfer from the coenzyme NADH to NAD was studied. Complexes [(η-CMeCHCH)Ir(L2)Cl]PF (2C) and [(η-CMeCHCH)Ir(L3)Cl]PF (3C) cause cell apoptosis and arrest the cell cycle at the G phase and G/M phase when HeLa cancer cells are treated with different IC concentrations of the complexes, and increase the amount of reactive oxygen species (ROS) dramatically, which appears to contribute to the anticancer activity. This class of organometallic Ir complexes has unusual features worthy of further exploration in the design of novel anticancer drugs.

The rational design of the ligands around transition metals has achieved success in the development of anticancer complexes. In this contribution, a series of organometallic half-sandwich iridium(iii) complexes with various corresponding counteranions have been prepared and characterized. The size and coordination ability of the counteranions exert a great influence on the chemical reactivity and anticancer activity of these complexes. The influence of the counteranions on the cell cycle, apoptosis, ROS and mitochondrial membrane potential is also discussed. This work has shown for the first time that the modification of counteranions can affect the anticancer activity of transition metal-based complexes.

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We herein report the synthesis, characterization, and anticancer activity of a series of iridium­(III) and ruthenium­(II) half-sandwich complexes of the type [(Cpx/arene)­M­(P^O)­Cl]­PF6 (M = Ir, Cpx = pentamethylcyclopentadienyl (Cp*) or its phenyl (Cpxph = C5Me4C6H5) or biphenyl (Cpxbiph = C5Me4C6H4C6H5) derivatives; M = Ru, arene = p-cymene (p-cym); P^O = phosphine phosphonic amide ligand (PPOA)). The X-ray crystal structures of all complexes, in which the ligand can form six-membered rings with the metal center, have been determined. All of the complexes show remarkable anticancer activities toward HeLa and A549 cancer cells, activities which are higher than that of the clinical anticancer drug cisplatin. The incorporation of phenyl substituents on the Cp* ring for iridium­(III) complexes results in little variation in their anticancer activities. These results can be attributed to the combinatorial action of the metal and PPOA ligand. Hydrolysis and DNA cleavage are not the major mechanisms of action. These complexes show potent catalytic activity in the transfer hydrogenation of NADH to NAD+. Additionally, complexes [(η5-C5Me5)­Ir­(P^O)­Cl]­PF6 (1) and [(η6-p-cym)­Ru­(P^O)­Cl]­PF6 (4) arrest cell cycles at S and G2/M phase and S phase, respectively. Complexes 1 and 4 both can induce apoptosis of HeLa cancer cells. Reactive oxygen species (ROS) and mitochondrial membrane potential tests were also performed to explore the mechanism of action. When the concentration of the complexes is increased, the amount of reactive oxygen species (ROS) increases dramatically and the mitochondrial membrane potential decreases significantly in HeLa cancer cells. Overall, cell stress including cell cycle perturbation, apoptosis induction, increase in ROS level, and loss of mitochondrial membrane potential contributes to the anticancer potency of these complexes. Interestingly, the use of confocal microscopy provides insights into the microscopic mechanism in which the typical and most active complex 1 can damage lysosomes. This type of complex represents a potent platform for development of metal anticancer drugs.

This work demonstrated how the chemical reactivity and anticancer activity as well as the selectivity of these half-sandwich N,N-chelated iridium(iii) complexes can be controlled and fine-tuned by the modification of the ligand electronic perturbations.