A Comparative Analysis of the In Vitro Anticancer Activity of Iridium(III) {η5-C5Me4R} Complexes with Variable R Groups.

Piano-stool iridium complexes based on the pentamethylcyclopentadienyl ligand (Cp*) have been intensively investigated as anticancer drug candidates and hold much promise in this setting. A systematic study aimed at outlining the effect of Cp* mono-derivatization on the antiproliferative activity is presented here. Thus, the dinuclear complexes [Ir(η5-C5Me4R)Cl(µ-Cl)]2 (R = Me, 1a; R = H, 1b; R = Pr, 1c; R = 4-C6H4F, 1d; R = 4-C6H4OH, 1e), their 2-phenylpyridyl mononuclear derivatives [Ir(η5-C5Me4R)(kN,kCPhPy)Cl] (2a-d), and the dimethylsulfoxide complex [Ir{η5-C5Me4(4-C6H4OH)}Cl2(κS-Me2S=O)] (3) were synthesized, structurally characterized, and assessed for their cytotoxicity towards a panel of six human and rodent cancer cell lines (mouse melanoma, B16; rat glioma, C6; breast adenocarcinoma, MCF-7; colorectal carcinoma, SW620 and HCT116; ovarian carcinoma, A2780) and one primary, human fetal lung fibroblast cell line (MRC5). Complexes 2b (R = H) and 2d (4-C6H4F) emerged as the most active ones and were selected for further investigation. They did not affect the viability of primary mouse peritoneal cells, and their tumoricidal action arises from the combined influence on cellular proliferation, apoptosis and senescence. The latter is triggered by mitochondrial failure and production of reactive oxygen and nitrogen species.

Sulfur-Coordinated Organoiridium(III) Complexes Exert Breast Anticancer Activity via Inhibition of Wnt/ß-Catenin Signaling.

The sulfur-coordinated organoiridium(III) complexes pbtIrSS and ppyIrSS, which contain C,N and S,S (dithione) chelating ligands, were found to inhibit breast cancer tumorigenesis and metastasis by targeting Wnt/ß-catenin signaling for the first time. Treatment with pbtIrSS and ppyIrSS induces the degradation of LRP6, thereby decreasing the protein levels of DVL2, ß-catenin and activated ß-catenin, resulting in downregulation of Wnt target genes CD44 and survivin. Additionally, pbtIrSS and ppyIrSS can suppress cell migration and invasion of breast cancer cells. Furthermore, both complexes show the ability to inhibit sphere formation and mediate the stemness properties of breast cancer cells. Importantly, pbtIrSS exerts potent anti-tumor and anti-metastasis effects in mouse xenograft models through the blockage of Wnt/ß-catenin signaling. Taken together, our results indicate that pbtIrSS has great potential to be developed as a breast cancer therapeutic agent with a novel mechanism.

Strategies for conjugating iridium(III) anticancer complexes to targeting peptides via copper-free click chemistry.

We report the synthesis and characterization of novel pentamethylcyclopentadienyl (Cp*) iridium(III) complexes [(Cp*)Ir(4-methyl-4'-carboxy-2,2'-bipyridine)Cl]PF6 (Ir-I), the product (Ir-II) from amide coupling of Ir-I to dibenzocyclooctyne-amine, and its conjugate (Ir-CP) with the cyclic nona-peptide c(CRWYDENAC). The familiar three-legged 'piano-stool' configuration for complex Ir-I was confirmed by its single crystal X-ray structure. Significantly, copper-free click strategy has been developed for site-specific conjugation of the parent complex Ir-I to the tumour targeting nona-cyclic peptide. The approach consisted of two steps: (i) the carboxylic acid group of the bipyridine ligand in complex Ir-I was first attached to an amine functionalized dibenzocyclooctyne group via amide formation to generate complex Ir-II; and (ii) the alkyne bond of dibenzocyclooctyne in complex Ir-II underwent a subsequent strain-promoted copper-free cycloaddition with the azide group of the modified peptide. Interestingly, while complex Ir-I was inactive towards A2780 human ovarian cancer cells, complex Ir-II exhibited moderate cytotoxic activity. Targeted complexes such as Ir-CP offer scope for enhanced activity and selectivity of this class of anticancer complexes.

Similarities and differences in d6 low-spin ruthenium, rhodium and iridium half-sandwich complexes: synthesis, structure, cytotoxicity and interaction with biological targets.

In this paper, we discussed the similarities and differences in d6 low-spin half-sandwich ruthenium, rhodium and iridium complexes containing 2,2'-biimidazole (H2biim). Three new complexes, {[RuCl(H2biim)(η6-p-cymene)]PF6}2·H2O (1), [(η5-Cp)RhCl(H2biim)]PF6 (2), and [(η5-Cp)IrCl(H2biim)]PF6 (3), were fully characterized by CHN, X-ray diffraction analysis, UV-Vis, FTIR, and 1H, 13C and 15N NMR spectroscopies. The complexes exhibit a typical pseudooctahedral piano-stool geometry, in which the aromatic arene ring (p-cymene or Cp) forms the seat, while the bidentate 2,2'-biimidazole and chloride ion form the three legs of the piano stool. Moreover, the cytotoxic activities of the compounds were examined in the LoVo, HL-60, MV-4-11, MCF-7 human cancer cell lines and BALB/3T3 normal mouse fibroblasts. Notably, the investigated complexes showed no cytotoxic effects towards the normal BALB/3T3 cell line compared to cisplatin, which has an IC50 value of 2.20 µg. Importantly, 1 displayed the highest activity against HL-60 (IC50 4.35 µg). To predict a binding mode, we explored the potential interactions of the metal complexes with CT-DNA and protein using UV absorption and circular dichroism. The obtained data suggest that the complexes could interact with CT-DNA via an outside binding mode. Moreover, binding of the complexes with the GSH via UV-Vis and ESI mass spectra was determined. Comparative studies have shown that the rhodium complex (2) is the most GSH reactive, which is probably responsible for its deactivation towards LoVo and MCF-7 tumour cells. The influence of the metal ion on the biological activity of isostructural Rh(III) and Ir(III) complexes was an important goal of the presented investigation.

Nucleus-Targeted Organoiridium-Albumin Conjugate for Photodynamic Cancer Therapy.

An organoiridium-albumin bioconjugate (Ir1-HSA) was synthesized by reaction of a pendant maleimide ligand with human serum albumin. The phosphorescence of Ir1-HSA was enhanced significantly compared to parent complex Ir1. The long phosphorescence lifetime and high 1 O2 quantum yield of Ir1-HSA are highly favorable properties for photodynamic therapy. Ir1-HSA mainly accumulated in the nucleus of living cancer cells and showed remarkable photocytotoxicity against a range of cancer cell lines and tumor spheroids (light IC50 ; 0.8-5 µm, photo-cytotoxicity index PI=40-60), while remaining non-toxic to normal cells and normal cell spheroids, even after photo-irradiation. This nucleus-targeting organoiridium-albumin is a strong candidate photosensitizer for anticancer photodynamic therapy.

Synthesis and characterization of tritium labeled N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-sulfamoylbenzamide.

N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-sulfamoylbenzamide is a potent C-C chemokine receptor 1 (CCR1) antagonist. The compound, possessing benzamide functionality, successfully underwent tritium/hydrogen (T/H) exchange with an organoiridium catalyst (Crabtree's catalyst). The labeling pattern in the product was studied with liquid chromatography-mass spectrometry, time-of-flight mass spectrometry, and (3) H-NMR. Overall, multiple labeled species were identified. In addition to the anticipated incorporation of tritium in the benzamide moiety, tritium labeling was observed in the valine portion of the molecule including substitution at its chiral carbon. Using authentic standards, liquid chromatography analysis of the labeled compound showed complete retention of stereochemical configuration.

Rhodium and Iridium Mediated C-H and O-H Bond Activation of Two Schiff Base Ligands: Synthesis, Characterization and Catalytic Properties of the Organometallic Complexes.

Reaction of [Rh(PPh3)3Cl] with two Schiff base ligands, viz. N-(2'-hydroxyphenyl)furan-2-aldimine (H 2 L 1 ) and N-(2'-hydroxyphenyl)thiophene-2-aldimine (H 2 L 2 ), in refluxing toluene affords organorhodium complexes of type [Rh(PPh3)2(L)Cl] (L = L1 and L2). Similar reaction with [Ir(PPh3)3Cl] yields organoiridium complexes of type [Ir(PPh3)2(L) (H)] (L = L1 and L2). Crystal structures of [Rh(PPh3)2(L1)Cl] and [Ir(PPh3)2(L2) (H)] have been determined, where the imine ligands are found to bind to the metal centers as CNO-donors. Structures of [Rh(PPh3)2(L2)Cl] and [Ir(PPh3)2(L1) (H)] have been optimized by density functional theory method. Formation of the organometallic complexes is believed to proceed via C-H and O-H bond activation of the imine ligands. All four complexes show intense absorptions in the visible and ultraviolet regions. Cyclic voltammetry on the complexes shows an oxidation on the positive side of SCE and a reduction on the negative side. The organoiridium complexes are found to efficiently catalyze Suzuki-type C-C cross coupling reactions.