Half-sandwich Iridium Complexes Research Articles

Highly potent half-sandwich iridium and ruthenium complexes as lysosome-targeted imaging and anticancer agents

In this study, six half-sandwich luminescent iridium (Ir) and ruthenium (Ru) anticancer complexes bearing P^P-chelating ligands 1,2-bis(diphenylphosphino)benzene (dppbz) and 1,8-bis(diphenylphosphino)naphthalene (dppn) were synthesized and characterized via1H-NMR spectroscopy, 31P-NMR spectroscopy, mass spectrometry, elemental analysis and X-ray crystallography. All the complexes displayed more potent anticancer activity than cisplatin towards A549 lung cancer cells and HeLa cervical cancer cells, especially the most potent iridium complex Ir3, which was 73 times more potent than cisplatin against A549 cells. Different from cisplatin, no nucleobase adducts of Ir3 were detected. With the help of the self-luminescence of complex Ir3 and confocal microscopy, it was observed that Ir3 efficiently penetrated into the A549 cells via energy-dependent active transport, and specifically accumulated in lysosomes, affected the permeabilization of the lysosomal membranes and induced caspase-dependent cell death through lysosomal damage. Both apoptosis and autophagy of the A549 cells were observed. The reactive oxygen species (ROS) elevation, reduction of the mitochondrial membrane potential and cell cycle arrest at the G0/G1 phase also contributed to the observed cytotoxicity of Ir3. We demonstrate that these half-sandwich Ir and Ru anticancer complexes have different anticancer mechanism of action from that of cisplatin, which can be developed as potential multifunctional theranostic platforms that combine bioimaging and anticancer capabilities.

Lysosome targeted drugs: rhodamine B modified N^N-chelating ligands for half-sandwich iridium(iii) anticancer complexes

We designed and synthesized four rhodamine-modified half-sandwich iridium complexes ([(η5-Cpx)Ir(N^N)Cl]PF6).

Anti-inflammatory activity of electron-deficient organometallics.

We report an evaluation of the cytotoxicity of a series of electron-deficient (16-electron) half-sandwich precious metal complexes of ruthenium, osmium and iridium ([Os/Ru(η6-p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolato)] (1/2), [Ir(η5-pentamethylcyclopentadiene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolato)] (3), [Os/Ru(η6-p-cymene)(benzene-1,2-dithiolato)] (4/5) and [Ir(η5-pentamethylcyclopentadiene)(benzene-1,2-dithiolato)] (6)) towards RAW 264.7 murine macrophages and MRC-5 fibroblast cells. Complexes 3 and 6 were found to be non-cytotoxic. The anti-inflammatory activity of 1–6 was evaluated in both cell lines after nitric oxide (NO) production and inflammation response induced by bacterial endotoxin lipopolysaccharide (LPS) as the stimulus. All metal complexes were shown to exhibit dose-dependent inhibitory effects on LPS-induced NO production on both cell lines. Remarkably, the two iridium complexes 3 and 6 trigger a full anti-inflammatory response against LPS-induced NO production, which opens up new avenues for the development of non-cytotoxic anti-inflammatory drug candidates with distinct structures and solution chemistry from that of organic drugs, and as such with potential novel mechanisms of action.

Cytotoxic Half-Sandwich Rh(III) and Ir(III) β-Diketonates.

A series of half-sandwich pentamethylcyclopentadienyl rhodium(III) and iridium(III) complexes [Cp*M(DBM/HDB/AVB)Cl] and [Cp*M(DBM/HDB/AVB)(PTA)][SO3CF3], where Cp* = pentamethylcyclopentadienyl, the proligands DBMH = dibenzoylmethane, HDBH = o-hydroxydibenzoylmethane, AVBH = avobenzone, and PTA = 1,3,5-triaza-7-phosphaadamantane, is reported. All the complexes were characterized by IR, 1H and 13C NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis, and DFT calculations. Five of the complexes have also been characterized in the solid-state by X-ray crystallography. The cytotoxicity of the complexes has been evaluated against human ovarian A2780 and A2780cisR cell lines and, with the only exception of complexes 1 and 2 that display a negligible cytotoxicity, exhibit moderate cytotoxicity toward both cancer cell lines. However, the complexes do not show cancer cell selectivity with respect to human embryonic kidney HEK293 cells.

Mononuclear half-sandwich iridium and rhodium complexes through C‒H activation: Synthesis, characterization and catalytic activity

A series of mononuclear half-sandwich cyclometalated group 9 (Ir and Rh) metal complexes were synthesized in good yields through metal-mediated C‒H bond activation. These air-stable C, N-chelate mode complexes have similar solid state structures. Both experimental results and DFT calculations confirmed that no binuclear complexes were generated in this reaction. The iridium complex 3a exhibited good catalytic activity for the reduction of both electron-rich and electron-poor aryl imines with low catalyst loading in the presence of formic acid/triethylamine (F/T) azeotropic mixture. All complexes were fully characterized by elemental analysis and IR and NMR spectroscopies. The structures of 1a, 1b, 2a, 3a and 4b (see chemical structure formula in Scheme 1 and Scheme 2) were further confirmed by single-crystal X-ray analysis.

Synthesis and anticancer evaluation of mono- and trinuclear half-sandwich rhodium(III) and iridium(III) complexes based on N,O-salicylaldiminato-sulfonated scaffolds

Mononuclear and trinuclear half-sandwich Rh(III) and Ir(III) complexes based on a sulfonated scaffold have been synthesised and characterised using NMR and IR spectroscopy, mass spectrometry and elemental analysis. The cytotoxicities of the compounds were evaluated against the WHC01 oesophageal cancer cell line, with a slight increase in activity observed upon coordination of the metal.

Synthesis, Photophysical Properties, and Living Cell Imaging of Theranostic Half-Sandwich Iridium–4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) Dyads

We report the synthesis, characterization, and photophysical properties of two new cyclometalated half-sandwich iridium(III) complexes having the general formula [(η5-Cp*)Ir(ppy)Z]PF6 where η5-Cp* = pentamethylcyclopentadienyl and ppy = 2-phenyl-pyridine as C∧N-chelating ligand and Z = 3- or 4-pyridyl-BODIPY (BODIPY = 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene dye containing a 3- or 4-pyridyl group at the meso position). The molecular structure of both complexes has been determined by X-ray crystallography. The photophysical properties of the dyads were investigated and compared to the pyridyl-BODIPY precursors. Antiproliferative studies demonstrated that one of the compounds was highly active with submicromolar IC50 on a panel of cancer cell lines. The replacement of the chlorido ligand by the pyridyl-BODIPY increased the lipophilicity of the complexes and slowed down the hydrolysis rate, which in turn increased the cytotoxicity of the metallodrug candidate. For the first time, cell uptake of one of the dyads was monitored by living cell fluorescence imaging. Interestingly, extremely fast internalization was observed the rate of which was temperature-dependent.

Half-sandwich hydrazine complexes of iridium: Preparation and reactivity

Chloro complexes IrCl2(η5-C5Me5)[P(OR)3] (1) (RMe, Et) were prepared by reacting dimer [IrCl2(η5-C5Me5)]2 with phosphites in alcohol. Treatment of 1 with R1NHNH2 gave monohydrazine complexes [IrCl(η5-C5Me5)(R1NHNH2){P(OR)3}]BPh4 (2, 3, 4) [R1H (2), Me (3), Ph (4)]. Bis(hydrazine) complexes [Ir(η5-C5Me5)(R1NHNH2)2{P(OR)3}](BPh4)2 (5, 6) were prepared by reacting chloro complexes first with AgOTf and then with an excess of hydrazine. Oxidation with Pb(OAc)4 at −40°C of both mono- and bis(hydrazine) complexes afforded phenyldiazene derivatives [IrCl(η5-C5Me5)(PhNNH){P(OR)3}]BPh4 (7) and [Ir(η5-C5Me5)(PhNNH)2{P(OR)3}](BPh4)2 (9). Bis(aryldiazene) [Ir(η5-C5Me5)(PhNNH)2{P(OR)3}](BPh4)2 (9, 10) were also prepared by allowing hydride IrH2(η5-C5Me5)[P(OR)3] (8) to react with aryldiazonium cations [ArN2]BF4. The complexes were characterised spectroscopically and by X-ray crystal structure determination of [IrCl(η5-C5Me5)(NH2NH2){P(OEt)3}]BPh4 (2b) and [IrCl(η5-C5Me5)(CH3NHNH2){P(OEt)3}]BPh4 (3b).

Pyridyl azine Schiff-base ligands exhibiting unexpected bonding modes towards ruthenium, rhodium and iridium half-sandwich complexes: Synthesis and structural studies

The reaction of multidentate azine Schiff-base ligands was investigated towards p-cymene ruthenium, Cp*Rh and Cp*Ir complexes. The reaction of [(arene)MCl2]2 (arene = p-cymene, Cp*; M = Ru, Rh and Ir) with azine Schiff-base ligands (L1-L3) in 1:2 M ratio led to the formation of mononuclear complexes of the type [(arene)M(L)Cl]+ whereas the reaction of [Cp*MCl2]2 (M = Rh/Ir) with azine Schiff-base ligands (L1-L3) in 1:1 M ratio afforded dinuclear rhodium and iridium complexes bearing formula [{Cp*MCl}2(μ-L)]+ (M = Rh/Ir). The ligands in dinuclear complexes exhibited interesting coordination modes towards the metal atom. The reaction of ligand L3 with [Cp*IrCl2]2 dimer yielded two coordination isomers whereas with [Cp*RhCl2]2 yielded exclusively one isomer. The molecular structure of both the isomers of the iridium complex has been established. In rhodium and iridium complexes the ligand L3 acted as uninegative pentadentate bridging ligand coordinating one metal center in a tridentate fashion and the other metal in a bidentate fashion. In the other isomer the ligand L3 behaved as uninegative tetradentate bridging ligand coordinating both iridium centers in a bidentate fashion. In the mononuclear complexes, the ligands are coordinated to the metal atom in a bidentate N∩N fashion through pyridine nitrogen and azine nitrogen. The ligand (L1 and L2) acted as tetradentate bridging ligand in dinuclear complexes. All these complexes were isolated and characterized by spectroscopic and analytical techniques.

Half-sandwich complexes of iridium and ruthenium containing cysteine-derived ligands.

The dimers [{(ηn-ring)MCl}2(μ-Cl)2] ((ηn-ring)M = (η5-C5Me5)Ir, (η6-p-MeC6H4iPr)Ru) react with the modified cysteines S-benzyl-l-cysteine (HL1) or S-benzyl-α-methyl-l-cysteine (HL2) affording cationic complexes of the formula [(ηn-ring)MCl(κ2N,S-HL)]Cl (1, 2) in good yield. Addition of NaHCO3 to complexes 1 and 2 gave equilibrium mixtures of neutral [(ηn-ring)MCl(κ2N,O-L)] (3, 4) and cationic [(ηn-ring)M(κ3N,O,S-L)]Cl (6Cl, 7Cl) complexes. Similar mixtures were obtained in one-pot reaction by successive addition of the modified cysteine and NaHCO3 to the above formulated dimers. Addition of the N-Boc substituted cysteine derivative S-benzyl-N-Boc-l-cysteine (HL3) and NaHCO3 to the dimers [{(ηn-ring)MCl}2(μ-Cl)2] affords the neutral compounds [(ηn-ring)MCl(κ2O,S-L3)] ((ηn-ring)M = (η5-C5Me5)Ir (5a), (η6-p-MeC6H4iPr)Ru (5b)). Complexes of the formula [(ηn-ring)MCl(κ3N,O,S-L)][SbF6] (6Sb-8Sb), in which the cysteine derivative acts as a tridentate chelate ligand, can be prepared by adding one equivalent of AgSbF6 to the solutions of compounds 5 or to the mixtures of complexes 3/6Cl and 4/7Cl. The amide proton of compounds 8aSb and 8bSb can be removed by addition of NaHCO3 affording the neutral complexes [(ηn-ring)M(κ3N,O,S-L3-H)] ((ηn-ring)M = (η5-C5Me5)Ir (9a), (η6-p-MeC6H4iPr)Ru (9b)). Complexes 9a and 9b can also be prepared by reacting the dimers [{(ηn-ring)MCl}2(μ-Cl)2] with HL3 and two equivalents of NaHCO3. The absolute configuration of the complexes has been established by spectroscopic and diffractometric means including the crystal structure determination of (RIr,RC,RS)-[(η5-C5Me5)Ir(κ3N,O,S-L1)][SbF6] (6aSb). The thermodynamic parameters associated with the epimerization at sulphur that the iridium compound [(η5-C5Me5)Ir(κ3N,O,S-L3-H)] (9a) undergoes have been determined through variable temperature 1H NMR studies.

Preparation of metalated azine complexes of iridium(iii)

The preparation of half-sandwich κ1-aldazine and κ1-ketazine complexes of iridium and their metalation reaction affording chelate κ2-azine derivatives are described. The photoluminescence properties of the chelate complexes are also described.

The discovery of half-sandwich iridium complexes containing lidocaine and (pyren-1-yl)ethynyl derivatives of phenylcyanamide ligands for photodynamic therapy.

The successful design, synthesis, characterization, photophysical properties and anticancer mechanistic studies of a series of half-sandwich cyclopentadienyl iridium(iii) complexes of the type [Cp*IrIII(LC)(L1)](PF6), 1, and [Cp*IrIII(LC)(L2)](PF6), 2, in which Cp* = pentamethylcyclopentadienyl, L1 = 4-(pyren-10-yl)ethynyl-phenylcyanamide, L2 = 4'-(pyren-10-yl)ethynyl-4-cyanamidobiphenyl, and LC = lidocaine, are reported for their application as photodynamic therapy (PDT) agents. The DNA binding, DNA photocleavage, cellular uptake, and apoptosis of the complexes have also been studied.

The synthesis and reactivity of 16-electron half-sandwich iridium complexes bearing a carboranylthioamide ligand.

A 16-electron half-sandwich Ir(iii) complex (Cp*Ir(SCN-Ph)C2H10H11, 2) featuring an o-carboranylthioamidate ligand has been synthesized, and its reactivity has been studied in detail. 2 reacts with donor ligands to afford a stable 18-electron configuration. Interestingly, the electron-deficient iridium complex 2 underwent an Ir-S bond insertion reaction with DMAD to produce an acetylene insertion product 5. Complex 2 also reacted with the [Cp*Ir] unit, produced by the reaction between [Cp*IrCl2]2 and AgOTf, to form a unique binuclear species with a metal-metal bond. Moreover, a selective B(6)-H bond activation of the o-carborane complex has also been achieved.

Half-sandwich ruthenium, rhodium and iridium complexes of triazolopyridine ligand: Synthesis and structural studies

Triazolopyridine ligand, {3-(2-pyridyl)-[1,2,3]triazolo[1,5-a]-pyridine}, L was synthesized by reaction of p-toulenesulphonyl hydrazine and dipyridyl ketone in the presence of acetic acid. Half-sandwich ruthenium, rhodium and iridium complexes [1–4] have been synthesized by reaction of [{(arene)MCl 2} 2] (arene = p-cymene/benzene/Cp* and M = Ru/Rh/Ir) with ligand L in methanol. The reaction in 1:2 (M:L) ratio has yielded all mononuclear cationic complexes such as [(arene)ML\(\kappa ^{2}_{\mathrm {N\cap N}}\)Cl]PF 6, where {(arene)M} = (p-cym)Ru (1), (benz)Ru (2), Cp*Rh (3) and Cp*Ir (4). All the complexes were characterized by spectral studies and the solid state structures of complexes, 1 and 3 were unambiguously determined by crystallographic studies. Triazolopyridine ligand, {3-(2-pyridyl)-[1,2,3]triazolo[1,5-a]-pyridine} L was synthesized by reaction of p-toulenesulphonyl hydrazine and dipyridyl ketone in the presence of acetic acid. Half-sandwich ruthenium, rhodium and iridium complexes [1-4] were synthesized by reaction of [{(arene)MCl2}2] (arene = p-cymene/benzene/Cp* and M = Ru/Rh/Ir) with ligand L in methanol. All the complexes were characterized by spectral studies and the solid state structures of two complexes were unambiguously determined by crystallographic studies.

Half-sandwich rhodium and iridium fragments and carboxylate ligands as building blocks for the formation of metallamacrocycles

A series of half-sandwich rhodium and iridium complexes containing carboxylate ligands were synthesized and characterized. Reactions between [Cp∗MCl2]2 (M = Ir or Rh) and 1,3,6-bis(2-pyridyl)-1,2,4,5-tetrazine (L1) gave binuclear complexes 1 and 2 under different conditions. The half-sandwich iridium and rhodium metallamacrocycles complexes 3–5 were constructed in a stepwise manner by the addition of carboxylate ligands (sodium acetate or the conjugate bases of pyrazine-2,3-dicarboxylic acid or 3-(2-pyridyl)acrylic acid) to the solution of the binuclear precursors prepared from the reactions of [Cp∗MCl2]2 (M = Rh or Ir) with linear N,N′-donor ligands (4,4′-bipyridine or trans-1,2-bis(4-pyridyl)ethylene), respectively. The structures of binuclear complexes and tetranuclear macrocycles were confirmed by elemental analysis, IR, 1H NMR spectroscopy and single-crystal X-ray diffraction.

Biological Potential of Halfsandwich Ruthenium(II) and Iridium (III) Complexes.

In vitro studies with the ruthenium(II) and analogous iridium(III) complexes [Ru(η6- p-cymene)Cl2{Ph2PCH2CH2CH2S(O)xPh-κP}], [Ru(η6-p-cymene)Cl{Ph2PCH2CH2CH2S(O)xPh- κP,κS}][PF6] (1-4), [Ir(η5-C5Me5)Cl2{Ph2PCH2CH2CH2S(O)xPh-κP}] and [Ir(η5-C5Me5)Cl{Ph2 PCH2CH2CH2S(O)xPh-κP,κS}][PF6] (5-8; x = 0, 1) revealed the high selectivity toward the 8505C, A253, MCF-7, SW480 and 518A2 cancer cell lines. Thus, the cationic ruthenium complex 4 proved to be the most selective one. In case of the neutral and cationic ruthenium complexes 1-4 the caspase-dependent apoptotic cell death was proven as the main cause of the drug's tumoricidal action on 8505C cell line.

Study of the Bonding Modes of Di‐2‐pyridyl ketoxime Ligand towards Ruthenium, Rhodium and Iridium Half Sandwich Complexes

AbstractThe bonding modes of the ligand di‐2‐pyridyl ketoxime towards half‐sandwich arene ruthenium, Cp*Rh and Cp*Ir complexes were investigated. Di‐2‐pyridyl ketoxime {pyC(py)NOH} react with metal precursor [Cp*IrCl2]2 to give cationic oxime complexes of the general formula [Cp*Ir{pyC(py)NOH}Cl]PF6 (1a) and [Cp*Ir{pyC(py)NOH}Cl]PF6 (1b), for which two coordination isomers were observed by NMR spectroscopy. The molecular structures of the complexes revealed that in the major isomer the oxime nitrogen and one of the pyridine nitrogen atoms are coordinated to the central iridium atom forming a five membered metallocycle, whereas in the minor isomer both the pyridine nitrogen atoms are coordinated to the iridium atom forming a six membered metallacyclic ring. Di‐2‐pyridyl ketoxime react with [(arene)MCl2]2 to form complexes bearing formula [(p‐cymene)Ru{pyC(py)NOH}Cl]PF6 (2); [(benzene)Ru{pyC(py)NOH}Cl]PF6 (3), and [Cp*Rh{pyC(py)NOH}Cl]PF6 (4). In case of complex 3 the ligand coordinates to the metal by using oxime nitrogen and one of the pyridine nitrogen atoms, whereas in complex 4 both the pyridine nitrogen atoms are coordinated to the metal ion. The complexes were fully characterized by spectroscopic techniques.

Improved scope and diastereoselectivity of C–H activation in an expanded supramolecular host

Chiral Ga4L6 assembly Ga4(LN)6 encapsulates cationic iridium half-sandwich complexes that activate aldehyde C–H bonds to form chiral, strongly bound piano-stool complexes. Herein, we report the expanded scope of the larger Ga4(LP)6 host in mediating this transformation. The larger assembly significantly improves both the scope and the diastereoselectivity of this organometallic transformation generally, while substrate-specific interactions demonstrate that host size is an important, but not definitive, factor in determining diastereoselectivity.

Half-sandwich rhodium and iridium metallamacrocycles constructed via C-H activation.

Half-sandwich rhodium and iridium complexes with carboxylic acid ligands were combined with pyrazine, 4,4'-bipyridine (bpy) or trans-1,2-bis(4-pyridyl)-ethylene (bpe) to give a series of tetranuclear macrocycles. The metallamacrocycles [(Cp*Rh)4()2(pyrazine)2][OTf]2 (), [(Cp*Rh)4()2(bpy)2][OTf]2 (), [(Cp*Rh)4()2(bpe)2][OTf]4 () and [(Cp*Ir)4()2 (pyrazine)2] () ( = 3-(2-pyridyl)acrylic acid, = 1,4-di(4-carboxyphenyl)benzene) were characterized by elemental analysis, NMR, IR and single-crystal X-ray analyses. Due to the different structures of the carboxylate ligands, the complexes , and were synthesized through double-site C-H activation, and complexes were obtained by one-site C-H activation.

Antibacterial, in vitro antitumor activity and structural studies of rhodium and iridium complexes featuring the two positional isomers of pyridine carbaldehyde picolinic hydrazone ligand

Half-sandwich organometallic rhodium and iridium complexes [1–6] have been synthesized with ligands L1 (L1=Pyridin-2-ylmethylene picolinichydrazine) and L2 (L2=Pyridin-3-ylmethylene picolinichydrazine). Treatment of [{Cp∗MCl2}2] (M=Rh/Ir) with L1 in methanol has yielded mononuclear cationic complexes such as [{Cp∗M(L1N∩N)Cl}]PF6 where {M=Rh (1) and Ir (2)} and dinuclear complexes such as [{(Cp∗MCl)2(L1N∩N, N∩N)}]PF6 where {M=Rh (3) and Ir (4)} in 1:2 and 1:1 metal dimer to ligand ratios respectively. Reactions of [{Cp∗MCl2}2] with L2 in both 1:2 and 1:1 metal dimer to ligand ratios have yielded two metalla-macrocyclic dinuclear and dicationic complexes such as [{Cp∗M(L2N∩NμN)}2](PF6)2 where {M=Rh (5) and Ir (6)}. Spectroscopic and crystallographic data were used to elucidate the structures of the synthesized complexes. The in vitro antitumor evaluation of the complexes 1 and 2 by fluorescence based apoptosis study revealed their antitumor activity against Dalton’s ascites lymphoma (DL) cells. The antibacterial evaluation of complexes 1, 2, 5 and 6 by agar well-diffusion method revealed their significant activity against the two species considered viz., Proteus vulgaris (MTCC 426) and Vibrio parahaemolyticus (MTCC 451) with zone of inhibition up to 43mm. The docking study with few key enzymes associated with cancer viz., ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II revealed their strong interactions with complexes under study. Complexes 1–6 exhibited a HOMO (highest occupied molecular orbital) – LUMO (lowest unoccupied molecular orbital) energy gap from 2.95eV to 3.59eV. TDDFT calculations explain the nature of electronic transitions and found well agreement with the experiments.