Half-sandwich Ir Research Articles

Selective B(3)-H Activation Affording Multinuclear Ir(III) Complexes with (o-Carboranyl)dithioester Ligands.

A method was developed to link two or three o-carborane moieties to form a series of carboranyl dithioester bridging ligands via in situ substitution of haloalkanes by tetraphenylphosphonium carboranyldithiocarboxylates. Based on these ligands, direct B-H activation without the assistance of Ag(I) and alkali was successfully achieved with half-sandwich Ir(III) substrate [Cp*IrCl2]2 to yield corresponding bimetallic or trimetallic complexes. Single crystal structure analyses of the B-H activated complexes and corresponding SnCl2-inserted derivatives confirm the selective B(3)-H activation in these complexes.

Development of Half-Sandwich Ru, Os, Rh, and Ir Complexes Bearing the Pyridine-2-ylmethanimine Bidentate Ligand Derived from 7-Chloroquinazolin-4(3H)-one with Enhanced Antiproliferative Activity.

Kinesin spindle protein (KSP) inhibitors are one of the most promising anticancer agents developed in recent years. Herein, we report the synthesis of ispinesib-core pyridine derivative conjugates, which are potent KSP inhibitors, with half-sandwich complexes of ruthenium, osmium, rhodium, and iridium. Conjugation of 7-chloroquinazolin-4(3H)-one with the pyridine-2-ylmethylimine group and the organometallic moiety resulted in up to a 36-fold increased cytotoxicity with IC50 values in the micromolar and nanomolar range also toward drug-resistant cells. All studied conjugates increased the percentage of cells in the G2/M phase, simultaneously decreasing the number of cells in the G1/G0 phase, suggesting mitotic arrest. Additionally, ruthenium derivatives were able to generate reactive oxygen species (ROS); however, no significant influence of the organometallic moiety on KSP inhibition was observed, which suggests that conjugation of a KSP inhibitor with the organometallic moiety modulates its mechanism of action.

Formic Acid Dehydrogenation through Ligand Design Strategy of Amidation in Half-Sandwich Ir Complexes.

A series of Cp*Ir (Cp* = pentamethylcyclopentadienyl) complexes with amidated 8-aminoquinoline ligands were synthesized and tested for formic acid (FA) dehydrogenation. These complexes showed improved activities compared to pristine 8-anminquinoline (L1). Specially, amidation changed the outer coordination sphere of the complex (3) bearing N-8-quinolinylformamide (L3), and 3 was proved to be a proton-responsive catalyst. Our experimental results and DFT calculations demonstrated that the deprotonated carbanion in L3 could interact with a water molecule to stabilize the transition states and lower the reaction energy barrier, which improved the reaction activity. A turnover frequency of 206250 h-1 was achieved by 3 under optimized conditions. This study presents a method to develop new ligands and modify the existing ligands for efficient FA dehydrogenation.

Recent Advancement in the Synthesis of Ir-Based Complexes.

Cancer is a devastating disease with over 100 types, including lung and breast cancer. Cisplatin and metal-based drugs are limited due to their drug resistance and side effects. Iridium-based compounds have emerged as promising candidates due to their unique chemical properties and resemblance to platinum compounds. The objective of this study is to investigate the synthesis and categorization of iridium complexes, with a particular emphasis on their potential use as anticancer agents. The major focus of this research is to examine the synthesis of these complexes and their relevance to the field of cancer treatment. The negligible side effects and flexibility of cyclometalated iridium(III) complexes have garnered significant interest. Organometallic half-sandwich Ir(III) complexes have notable benefits in cancer research and treatment. The review places significant emphasis on categorizing iridium complexes according to their ligand environment, afterward considering the ligand density and coordination number. This study primarily focuses on several methods for synthesizing cyclometalated and half-sandwich Ir complexes, divided into subgroups based on ligand denticity. The coordination number of iridium complexes determines the number of ligands coordinated to the central iridium atom, which impacts their stability and reactivity. Understanding these complexes is crucial for designing compounds with desired properties and investigating their potential as anticancer agents. Cyclometalated iridium(III) complexes, which contain a meta-cycle with the E-M-C order σ bond, were synthesized in 1999. These complexes have high quantum yields, significant stock shifts, luminescence qualities, cell permeability, and strong photostability. They have been promising in biosensing, bioimaging, and phosphorescence of heavy metal complexes.

Half-Sandwich Iridium(III), Rhodium(III), and Ruthenium(II) Complexes Chelating Hybrid sp2-N/sp3-N Donor Ligands to Achieve Improved Anticancer Selectivity.

The biological efficacy of half-sandwich platinum group organometallic complexes of the formula [(η5-Cpx)/(η6-arene)M(XY)Cl]0/+ (XY = bidentate ligands; Cpx = functionalized cyclopentadienyl; M = Ir, Rh, Ru, Os) has received considerable attention due to the significance of the metal center, chelating ligand, and Cpx/arene moieties in defining their anticancer potency and selectivity. With a facile access to the BIAN-derived imine-amine ligands using alkylaluminum as the reductant, we herein described the preparation and characterization of 16 half-sandwich Ir(III), Rh(III), and Ru(II) complexes chelating the hybrid sp2-N/sp3-N donor ligand. A nonplanar five-member metallacycle was confirmed by X-ray single-crystal structures of Ir1-Ir3, Ir7, Rh1, Ru1, and Ru4. The attempt to prepare imine-amido complexes using a base as the deprotonating agent led to the mixture of imine-amine complexes, within which the leaving group Cl- was displaced, and 16-electron imine-amido complexes without Cl-. The half-sandwich imine-amine complexes in this system underwent rapid hydrolysis in aqueous solution, exhibited weak photoluminescence, and showed the ability of binding to CT-DNA and BSA. The cytotoxicity of all imine-amine complexes against A549 lung cancer cell lines, HeLa cervical cancer cell lines, and 4T1 mouse breast cancer cells was determined by an MTT assay. The IC50 values of these complexes were in a range of 5.71-67.28 μM. Notably, most of these complexes displayed improved selectivity toward A549 cancer cells versus noncancerous BEAS-2B cells in comparison with the corresponding α-diimine complexes chelating the sp2-N/sp2-N donor ligand, which have been shown no selectivity in our previous report. The anticancer selectivity of these complexes appeared to be related to the redox-based mechanism including the catalytic oxidation of NADH to NAD+, reactive oxygen species (ROS) generation, and depolarization of the mitochondrial membrane. Further, inducing apoptosis of these complexes in A549 cancer cells and BEAS-2B normal cells also correlated with their anticancer selectivity, indicating the apoptosis mode of cell death in this system. In addition, these complexes could enter A549 cells via energy-dependent pathway and were able to impede the in vitro migration of A549 cells.

Insights into the binding of half-sandwich phosphino Ir(III) and Ru(II) complexes to deoxyribonucleic acid, albumin and apo-transferrin: Experimental and theoretical investigation

A group of cytotoxic half-sandwich iridium(III) (Ir(η5-Cp*)Cl2PPh2CH2OH (IrPOH)), (Ir(η5-Cp*)Cl2P(p-OCH3Ph)2CH2OH (IrMPOH)), and ruthenium(II) (Ru(η6-p-cymene)Cl2PPh2CH2OH (RuPOH), Ru(η6-p-cymene)Cl2P(p-OCH3Ph)2CH2OH (RuMPOH)) complexes with phosphine ligands exhibit the ability to (i) slow hydrolysis which is reversed by adding a high NaCl concentration; (ii) oxidation of NADH to NAD+; (iii) induction of cytotoxicity towards various cancer cell lines. Furthermore, we found that RuPOH and RuMPOH selectively inhibit the proliferation of skin cancer cells (WM266-4) while Ir(III) complexes were found to be moderate against prostate cancer cells (DU-145). Herein, to elucidate the cytotoxic effects, we investigated the interaction of these complexes with DNA and serum proteins by gel electrophoresis, fluorescence spectroscopy, and molecular docking studies. Fluorescence spectroscopic data (calf thymus DNA: CT-DNA titration), together with analysis of DNA fragmentation (gel electrophoresis) and molecular docking provided evidence for the multimodal interaction of Ir(III) and Ru(III) complexes with DNA with predominance of intercalation and minor groove binding. All examined complexes caused single-stranded cleavage of the sugar–phosphate backbone of plasmid DNA. The affinity of the complexes for apo-transferrin (apo-Tf) and human serum albumin (HSA) was evaluated by fluorescence emission spectroscopy to calculate the binding constants which suggested a tight and reversible binding. Moreover, ruthenium complexes can mimic the binding of iron compounds to specific biomolecules such as albumin and transferrin better than iridium complexes. In silico study indicate that complexes mostly bind to (i) apo-Tf with a preference for a single binding site and/or (ii) to dock within all the four predicted binding sites of HSA with the predominance of site I which include tryptophan residues of HSA. This class of ruthenium(II) and iridium(III) complexes has unusual features worthy of further exploration in the design of novel anticancer drugs.

Impact of the central atom and halido ligand on the structure, antiproliferative activity and selectivity of half-sandwich Ru(II) and Ir(III) complexes with a 1,3,4-thiadiazole-based ligand.

Half-sandwich complexes [Ru(η6-pcym)(L1)X]PF6 (1, 3) and [Ir(η5-Cp*)(L1)X]PF6 (2, 4) featuring a thiadiazole-based ligand L1 (2-(furan-2-yl)-5-(pyridin-2-yl)-1,3,4-thiadiazole) were synthesized and characterized by varied analytical methods, including single-crystal X-ray diffraction (X = Cl or I, pcym = p-cymene, Cp* = pentamethylcyclopentadienyl). The structures of the molecules were analysed and interpreted using computational methods such as Density Functional Theory (DFT) and Quantum Theory of Atoms in Molecules (QT-AIM). A 1H NMR spectroscopy study showed that complexes 1-3 exhibited hydrolytic stability while 4 underwent partial iodido/chlorido ligand exchange in phosphate-buffered saline. Moreover, 1-4 demonstrated the ability to oxidize NADH (reduced nicotinamide adenine dinucleotide) to NAD+ with Ir(III) complexes 2 and 4 displaying higher catalytic activity compared to their Ru(II) analogues. None of the complexes interacted with reduced glutathione (GSH). Additionally, 1-4 exhibited greater lipophilicity than cisplatin. In vitro biological analyses were performed in healthy cell lines (CCD-18Co colon and CCD-1072Sk foreskin fibroblasts) as well as in cisplatin-sensitive (A2780) and -resistant (A2780cis) ovarian cancer cell lines. The results indicated that Ir(III) complexes 2 and 4 had no effect on human fibroblasts, demonstrating their selectivity. In contrast, complexes 1 and 4 exhibited moderate inhibitory effects on the metabolic and proliferation activities of the cancer cells tested (selectivity index SI > 3.4 for 4 and 2.6 for cisplatin; SI = IC50(A2780)/IC50(CCD-18Co)), including the cisplatin-resistant cancer cell line. Based on these findings, it is possible to emphasize that mainly complex 4 could represent a further step in the development of selective and highly effective anticancer agents, particularly against resistant tumour types.

Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand.

Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular targets, leading to undesirable side effects. Herein we present a systematic study on structure-activity relationships of eight arylbenzazole-based Iridium(III) complexes of type [IrCl(Cp*)], that have revealed the role of each atom of the ancillary ligand in the physical chemistry properties, cytotoxicity and mechanism of biological action. Neutral complexes, especially those bearing phenylbenzimidazole (HL1 and HL2), restrict the binding to DNA and albumin. One of them, complex 1[C,NH-Cl], is the most selective one, does not bind DNA, targets exclusively the mitochondria, disturbs the mitochondria membrane permeability inducing proton leak and increases ROS levels, triggering the molecular machinery of regulated cell death. In mice with orthotopic lung tumors, the administration of complex 1[C,NH-Cl] reduced the tumor burden. Cancers are more vulnerable than normal tissues to a treatment that harnesses mitochondrial dysfunction. Thus, complex 1[C,NH-Cl] characterization opens the way to the development of new compounds to exploit this vulnerability.

Synthesis of P- and S-Stereogenic Compounds via Enantioselective C–H Functionalization

AbstractTransition metal-catalyzed enantioselective C–H functionalization has emerged as an efficient and powerful strategy to access various chiral molecules. Recently, this strategy has also provided a complementary pathway to the construction of P- and S-stereogenic compounds. In this short review, we summarize the development and applications of various catalytic systems: Pd(II)/mono-N-protected amino acids (MPAA), Pd(0)/trivalent phosphorus chiral ligands, chiral cyclopentadienyl-ligated metal catalysts [CpxM(III)] (M = Rh, Ir), half-sandwich d6 Ir(III) and Ru(II) with a chiral carboxylic acid (CCA) ligand, Ir(I)/chiral bidentate boryl ligand, and Ir(I)/chiral cation, for accessing these chiral compounds via enantioselective C–H functionalization. 1 Introduction2 Pd(II)/Mono-N-protected Amino Acids3 Pd(0)/Trivalent Phosphorus Chiral Ligands4 Chiral Cyclopentadienyl-Ligated Metal Catalysts [CpxM(III)] (M = Rh, Ir)5 Half-sandwich d6 Ir(III) and Ru(II) with a Chiral Carboxylic Acid (CCA) Ligand6 Ir(I)/Chiral Bidentate Boryl Ligand7 Ir(I)/Chiral Cation8 Conclusion and Outlook

Investigating the antiplasmodial activity of substituted cyclopentadienyl rhodium and iridium complexes of 2-(2-pyridyl)benzimidazole

Six cationic half-sandwich Ir(III) and Rh(III) complexes (C1-C6) were synthesised by reaction of 2-(2-pyridyl)benzimidazole with the appropriate chloro-bridged dimers. All complexes were fully characterised using standard spectroscopic techniques and their purity confirmed by RP-HPLC. The molecular structures of these complexes were elucidated using single-crystal X-ray diffraction. Depending on the substituted cyclopentadienyl (Cpx) ligands, the complexes crystallized with an orthorhombic (Cpx = pentamethylcyclopentadienyl), monoclinic (Cpx = tetramethylphenylcyclopentadienyl) or triclinic (Cpx = tetramethylbiphenylcyclopentadienyl) crystal system. All complexes displayed good solubility in PBS and HEPES buffers within the concentration range used for the in vitro inhibitory screening. Using proton NMR experiments, the stability of the complexes in water was monitored at 37 °C and all complexes were resistant to displacement of their chlorido ancillary ligands by water. In vitro screening against the 3D7 chloroquine-sensitive and Dd2 multi-drug-resistant strains of Plasmodium falciparum revealed all complexes exhibited moderate to good potency. Complex C6 emerged as the most promising candidate with IC50 values of 0.75 ± 0.11 and 0.42 ± 0.055 µM against the 3D7 and Dd2 strains, respectively. The newly synthesised complexes were not cytotoxic to Human Embryonic Kidney cells.

Anticancer half-sandwich Ir(iii) complex and its interaction with various biomolecules and their mixtures – a case study with ascorbic acid

An anticancer azo bond-containing half-sandwich Ir(iii) complex oxidizes ascorbate to dehydroascorbate, and ascorbate recovers in the presence of reduced glutathione.

Iridium Azocarboxamide Complexes: Variable Coordination Modes, C–H Activation, Transfer Hydrogenation Catalysis, and Mechanistic Insights

Azocarboxamides, a special class of azo ligands, display intriguing electronic properties due to their versatile binding modes and coordination flexibility. These properties may have significant implications for their use in homogeneous catalysis. In the present report, half-sandwich Ir–Cp* complexes of two different azocarboxamide ligands are presented. Different coordination motifs of the ligand were realized using base and chloride abstracting ligand to give N∧N-, N∧O-, and N∧C-chelated monomeric iridium complexes. For the azocarboxamide ligand having methoxy substituted at the phenyl ring, a mixture of N∧C-chelated mononuclear (Ir-5) and N∧N,N∧C-chelated dinuclear complexes (Ir-4) were obtained by activating the C–H bond of the aryl ring. No such C–H activation was observed for the ligand without the methoxy substituent. The molecular identity of the complexes was confirmed by spectroscopic analyses, while X-ray diffraction analyses further confirmed three-legged piano-stool structure of the complexes along with the above binding modes. All complexes were found to exhibit remarkable activity as precatalysts for the transfer hydrogenation of carbonyl groups in the presence of a base, even at low catalyst loading. Optimization of reaction conditions divulged superior catalytic activity of Ir-3 and Ir-4 complexes in transfer hydrogenation over the other catalysts. Investigation of the influence of binding modes on the catalytic activity along with wide range substrates, tolerance to functional groups, and mechanistic insights into the reaction pathway are also presented. These are the first examples of C–H activation in azocarboxamide ligands.

Anticancer Activity of Half-Sandwich Ru, Rh and Ir Complexes with Chrysin Derived Ligands: Strong Effect of the Side Chain in the Ligand and Influence of the Metal.

An important challenge in the field of anticancer chemotherapy is the search for new species to overcome the resistance of standard drugs. An interesting approach is to link bioactive ligands to metal fragments. In this work, we have synthesized a set of p-cymene-Ru or cyclopentadienyl-M (M = Rh, Ir) complexes with four chrysin-derived pro-ligands with different -OR substituents at position 7 of ring A. The introduction of a piperidine ring on chrysin led to the highly cytotoxic pro-ligand HL4 and its metal complexes L4-M (SW480 and A549 cell lines, cytotoxic order: L4-Ir > L4-Ru ≈ L4-Rh). HL4 and its complexes induce apoptosis and can overcome cis-platinum resistance. However, HL4 turns out to be more cytotoxic in healthy than in tumor cells in contrast to its metal complexes which displayed higher selectivity than cisplatin towards cancer cells. All L4-M complexes interact with double stranded DNA. Nonetheless, the influence of the metal is clear because only complex L4-Ir causes DNA cleavage, through the generation of highly reactive oxygen species (1O2). This result supports the hypothesis of a potential dual mechanism consisting of two different chemical pathways: DNA binding and ROS generation. This behavior provides this complex with a great effectivity in terms of cytotoxicity.

Bioactive half-sandwich Rh and Ir bipyridyl complexes containing artemisinin

Reaction of dihydroartemisinin (DHA) with 4-methyl-4′-carboxy-2,2′-bipyridine yielded the new ester derivative L1. Six novel organometallic half-sandwich chlorido Rh(III) and Ir(III) complexes (1–6) containing pentamethylcyclopentadienyl, (Cp*), tetramethylphenylcyclopentadienyl (Cpxph), or tetramethylbiphenylcyclopentadienyl (Cpxbiph), and N,N-chelated bipyridyl group of L1, have been synthesized and characterized. The complexes were screened for inhibitory activity against the Plasmodium falciparum 3D7 (sensitive), Dd2 (multi-drug resistant) and NF54 late stage gametocytes (LSGNF54), the parasite strain Trichomonas vaginalis G3, as well as A2780 (human ovarian carcinoma), A549 (human alveolar adenocarcinoma), HCT116 (human colorectal carcinoma), MCF7 (human breast cancer) and PC3 (human prostate cancer) cancer cell lines. They show nanomolar antiplasmodial activity, outperforming chloroquine and artemisinin. Their activities were also comparable to dihydroartemisinin. As anticancer agents, several of the complexes showed high inhibitory effects, with Ir(III) complex 3, containing the tetramethylbiphenylcyclopentadienyl ligand, having similar IC50 values (concentration for 50% of maximum inhibition of cell growth) as the clinical drug cisplatin (1.06–9.23 μM versus 0.24–7.2 μM, respectively). Overall, the iridium complexes (1–3) are more potent compared to the rhodium derivatives (4–6), and complex 3 emerges as the most promising candidate for future studies.

Dinuclear half-sandwich Ir(III) complexes containing 4,4′-methylenedianiline-based ligands: Synthesis, characterization, cytotoxicity

Three dinuclear half-sandwich iridium(III) complexes [Ir2(μ-L1)(η5-Cp*)2Cl2](PF6)2 (1), [Ir2(μ-L2)(η5-Cp*)2Cl2](PF6)2 (2) and [Ir2(μ-L3)(η5-Cp*)2Cl2](PF6)2 (3) with tetradentate 4,4′-methylenedianiline-based N-donor ligands (L1–L3) were prepared and characterized by NMR spectroscopy, elemental analysis, mass spectrometry and FTIR spectroscopy. Complex 3 was hydrolytically less stable in 20% DMSO-d6/80% D2O than 1 and 2, while all the studied complexes were stable in the same mixture of solvents in the presence of PBS (pH 7.4). In addition, complexes 1–3 converted coenzyme NADH to its oxidized form (NAD+). Cytotoxicity of 1–3 was evaluated on five human cancer cell lines, in particular lung carcinoma (A549), hepatocellular carcinoma (HepG2), melanoma (A375), prostate carcinoma (DU-145) and breast carcinoma (MCF-7). The best-performing complex 2 showed comparable cytotoxicity to conventional cisplatin against the A549 and HepG2 cell lines.

Unexpected solution behaviour of ester-functionalized half-sandwich Ru(II) and Ir(III) complexes.

Complexes [Ru(η6-pcym)(bpydca)Cl]PF6 (Rudca) and [Ir(η5-Cp*)(bpydca)Cl]PF6 (Irdca) were developed as model compounds for the investigation of multi-targeted ester-functionalized half-sandwich ruthenium(ii) and iridium(iii) complexes; pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), bpydca = 2,2'-bipyridine-4,4'-diyldimethanediyl bis(dichloroacetate), Cp* = pentamethylcyclopentadienyl. Aiming to understand the in-solution behaviour of these first-in-class complexes containing the pyruvate dehydrogenase kinase inhibitor dichloroacetate (dca) as the terminal bioactive substituent, several experiments were performed under aqueous conditions for Rudca and Irdca, as well as for compounds [Ru(η6-pcym)(bpyOH)Cl]PF6 (RuOH) and [Ir(η5-Cp*)(bpyOH)Cl]PF6 (IrOH), and acetyl analogues [Ru(η6-pcym)(bpyac)Cl]PF6 (Ruac) and [Ir(η5-Cp*)(bpyac)Cl]PF6 (Irac) bearing a different (biologically inactive) terminal substituent; bpyOH = 2,2'-bipyridine-4,4'-diyldimethanol, bpyac = 2,2'-bipyridine-4,4'-diyldimethanediyl diacetate. The experiments were also conducted in the presence of porcine liver esterase (PLE). All the six complexes were characterized by relevant techniques (e.g., NMR and mass spectrometry), including a single-crystal X-ray analysis of complexes Rudca, Ruac, RuOH and IrOH. Although designed as model compounds, Rudca, Irdca, RuOH and IrOH were also screened for their antiproliferative activity in four human cancer cell lines (HCT116 colon carcinoma, MDA-MB-231 and MCF-7 breast adenocarcinomas, DU145 prostate carcinoma), where the tested complexes did not show any effect (IC50 > 100 μM).

WITHDRAWN: Cytotoxic and antimicrobial effects of half-sandwich Ir(III) complexes containing N,P-donor phosphanylalkylamine ligands

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Direct reductive amination of ketones with ammonium salt catalysed by Cp*Ir(III) complexes bearing an amidato ligand.

A series of half-sandwich Ir(III) complexes 1-6 bearing an amidato bidentate ligand were conveniently synthesized and applied to the catalytic Leuckart-Wallach reaction to produce racemic α-chiral primary amines. With 0.1 mol% of complex 1, a broad range of ketones, including aryl ketones, dialkyl ketones, cyclic ketones, α-keto acids, α-keto esters and diketones, could be transformed to their corresponding primary amines with moderate to excellent yields (40%-95%). Asymmetric transformation was also attempted with chiral Ir complexes 3-6, and 16% ee of the desired primary amine was obtained. Despite the unsatisfactory enantio-control achieved so far, the current exploration might stimulate more efforts towards the discovery of better chiral catalysts for this challenging but important transformation.

Experimental and theoretical characterization of the strong effects on DNA stability caused by half-sandwich Ru(II) and Ir(III) bearing thiabendazole complexes.

The synthesis and characterization of two half-sandwich complexes of Ru(II) and Ir(III) with thiabendazole as ancillary ligand and their DNA binding ability were investigated using experimental and computational methods. 1H NMR and acid-base studies have shown that aquo-complexes are the reactive species. Kinetic studies show that both complexes bind covalently to DNA through the metal site and non covalently through the ancillary ligand. Thermal stability studies, viscosity, circular dichroism measurements and quantum chemical calculations have shown that the covalent binding causes breaking of the H-bonding between base pairs, bringing about DNA denaturation and compaction. Additionally, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations shed light into the binding features of the Ru(II) and Ir(III) complexes and their respective enantiomers toward double-helical DNA, highlighting the important role played by the NˆN ancillary ligand once the complexes are covalently linked to DNA. Moreover, metal quantification in the nucleus of SW480 colon adenocarcinoma cells were carried out by inductively coupled plasma-mass spectrometry (ICP-MS), both complexes are more internalized than cisplatin after 4h of exposition. However, in spite of the dramatic changes in the helicity of the DNA secondary structure induced by these complexes and their nuclear localization, antiproliferative studies have revealed that both, Ru(II) and Ir(III) complexes, cannot be considered cytotoxic. This unexpected behavior can be justified by the fast formation of aquo-complexes, which may react with components of the cell culture medium or the cytoplasm compartment in such a way that they may become deactivated before reaching DNA.

Unveiling the anti-cancer mechanism for half-sandwich and cyclometalated Ir(iii)-based complexes with functionalized α-lipoic acid.

Alpha lipoic acid (LA) is a natural compound and coenzyme with sufficient safety information for serving as a promising anticancer agent. To further clarify the mechanism of action (MoA), two Ir(iii) complexes with the functionalized α-lipoic acid (N∧N-LA, N∧N, 2,2-bipyridine derivative), namely Ir1 and Ir2, were synthesized, where Ir1 possessed a half-sandwich structure with the formula [Ir(Cp*)(N∧N-LA)Cl]PF6 (Cp* = 1,2,3,4,5-pentamethyl-cyclopentadiene) and Ir2 possessed the cyclometalated structure with the formula [Ir(C∧N)2(N∧N-LA)]PF6 (C∧N = 2-phenylpyridine). Even though both complexes were constructed based on the same N∧N-LA ligand, Ir1 showed no cytotoxicity (IC50 > 200 μM), which was due to its low lipophilicity for hard penetration into the cancer cells, easy hydrolysis, and reaction with GSH. Ir2 exhibited excellent cytotoxicity (IC50 = 3.43–6.74 μM) toward diverse cancer cell lines in vitro and a promising ability to overcome the cisplatin-resistance in A549R cells. The anticancer mechanism of Ir2 in A549 cells was investigated in detail, and it was found it could localize and accumulate in the lysosomes of A549 cells, induce ROS, arrest the cycle at G0/G1, and lead to cell death by autophagy. Comparison with Ir-NH2 ([Ir(C∧N)2(N∧N-NH2)]PF6) demonstrated that introduction of the LA ligand to Ir2 could highly enhance the cytotoxicity and help to overcome the cisplatin-resistance. This study of the half-sandwich and cyclometalated Ir(iii)-based anticancer agents highlighted the different MoAs toward cancer cells and provided new insights for understanding their structure–property relationships.