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Ruthenium complexes have been investigated for various biological applications by virtue of their radical scavenging, DNA binding, receptor binding, and cytotoxic abilities; especially the possible potential application of these complexes in photodynamic therapy (PDT). This study focuses on the synthesis, structural characterization and biological application (pertaining to its cytotoxicity and radical generation) of ruthenium complexed with salicylaldehyde fumaryl-dihydrazone (slfhH₄ ), salicylaldehyde glutaryl-di-hydrazone (slfgH₄ ) and 2,2'-bipyridine (bpy). During the synthesis, the anticipated complex was precipitated out but as serendipity, Ruthenium(II) tris (2,2'-bipyridyl) monochloride nonahydrate {[Ru(bpy)₃ ]²⁺ .Cl.9H₂ O} (RBMN) and Ruthenium(II) tris (2,2'-bipyridyl) monochloride septahydrate {[Ru(bpy)₃ ]²⁺ .Cl.7H₂ O}(RBMS) were crystallized from the filtrate. The crystal structure of complexes RBMN and RBMS were determined by a single-crystal X-ray diffraction methods and it showed that chlorine anion lies at the crystallographic axis and forms a halogen hydrogen-bonded organic framework (XHOF) to provide the stability. In comparison with similar structures in Cambridge Crystallographic Data Center (CCDC) revealed that the nature of the XHOF framework and the layered packing are conserved. The compounds showed excellent cytotoxic ability (against L6 cells) and the nitro blue tetrazolium (NBT) assay upon irradiation to light revealed its ability to produce reactive oxygen species (ROS). The presence of partially occupied water molecules in the layered organization within the crystal packing mimics the release of ROS resulting in cytotoxicity. The structural results together with the biological data make these complexes interesting candidates for potential photosensitizers for PDT applications. Show less

Novel full-sandwich (η⁵-Cp)-Ru-paraphenylene complexes with the general formula [(η⁵-Cp)_nRu(η⁶-L)](PF₆)_n where n = 1-3 and L = biphenyl, p-terphenyl and p-quaterphenyl, were synthesized and characterized by means of spectroscopic and analytical techniques. The structures of the complexes [(η⁵-Cp)Ru(η⁶-biphenyl)](PF₆) (1), [(η⁵-Cp)Ru(η⁶-terphenyl)](PF₆) (3) and [(η⁵-Cp)₂Ru(η⁶-terphenyl)](PF₆)₂ (4) was determined by X-ray single crystal methods. The interaction of the complexes [(η⁵-Cp)Ru(η⁶-quaterphenyl)]Cl, (6)Cl, and [(η⁵-Cp)₂Ru(η⁶-quaterphenyl)]Cl₂, (7)Cl₂, with the DNA duplex d(5'-CGCGAATTCGCG-3')₂ was studied using NMR techniques. The results showed that both complexes interacted non-specifically with both the minor and major grooves of the helix. Specifically, (6)Cl exhibited partial binding through intercalation between the T7 and T8 bases of the sequence without disrupting the C-G and A-T hydrogen bonds. Fluorometric determination of the complexes' binding constants revealed a significant influence of the number of connected phenyl rings in the paraphenylene ligand (L) on the binding affinity of their complexes with the d(5'-CGCGAATTCGCG-3')₂. The complexes (6)Cl and (7)Cl₂ were found to be highly cytotoxic against the A549 lung cancer cell line, with complex (6) being more effective than (7) (IC₅₀ for (6)Cl: 17.45 ± 2.1 μΜ, IC₅₀ for (7)Cl₂: 65.83 ± 1.8 μΜ) and with a selectivity index (SI) (SI for (6)Cl: 1.1 and SI for (7)Cl₂: 4.8). Show less

Eight rhenium(I) tricarbonyl aqua complexes with the general formula fac-[Re(CO)₃(N,N'-bid)(H₂O)][NO₃] (1-8), where N,N'-bid is (2,6-dimethoxypyridyl)imidazo[4,5-f]1,10-phenanthroline (L1), (indole)imidazo[4,5-f]1,10-phenanthroline (L2), (5-methoxyindole)-imidazo[4,5-f]1,10-phenanthroline (L3), (biphenyl)imidazo[4,5-f]1,10-phenanthroline (L4), (fluorene)imidazo[4,5-f]1,10-phenanthroline (L5), (benzo[b]thiophene)imidazo[4,5-f]1,10-phenanthroline (L6), (5-bromothiazole)imidazo[4,5-f]1,10-phenanthroline (L7), and (4,5-dimethylthiophene)imidazo[4,5-f]1,10-phenanthroline (L8), were synthesized and characterized using ¹H and ¹³C{¹H} NMR, FT-IR, UV/Vis absorption spectroscopy, and ESI-mass spectrometry, and their purity was confirmed by elemental analysis. The stability of the complexes in aqueous buffer solution (pH 7.4) was confirmed by UV/Vis spectroscopy. The cytotoxicity of the complexes (1-8) was then evaluated on prostate cancer cells (PC3), showing a low nanomolar to low micromolar in vitro cytotoxicity. Worthy of note, three of the Re(I) tricarbonyl complexes showed very low (IC₅₀ = 30-50 nM) cytotoxic activity against PC3 cells and up to 26-fold selectivity over normal human retinal pigment epithelial-1 (RPE-1) cells. The cytotoxicity of both complexes 3 and 6 was lowered under hypoxic conditions in PC3 cells. However, the compounds were still 10 times more active than cisplatin in these conditions. Additional biological experiments were then performed on the most selective complexes (complexes 3 and 6). Cell fractioning experiments followed by ICP-MS studies revealed that 3 and 6 accumulate mostly in the mitochondria and nucleus, respectively. Despite the respective mitochondrial and nuclear localization of 3 and 6, 3 did not trigger the apoptosis pathways for cell killing, whereas 6 can trigger apoptosis but not as a major pathway. Complex 3 induced a paraptosis pathway for cell killing while 6 did not induce any of our other tested pathways, namely, necrosis, paraptosis, and autophagy. Both complexes 3 and 6 were found to be involved in mitochondrial dysfunction and downregulated the ATP production of PC3 cells. To the best of our knowledge, this report presents some of the most cytotoxic Re(I) carbonyl complexes with exceptionally low nanomolar cytotoxic activity toward prostate cancer cells, demonstrating further the future viability of utilizing rhenium in the fight against cancer. Show less

Title: Ruthenium(II) polypyridyl complexes with visible light-enhanced anticancer activity and multimodal cell imaging. Abstract: Ruthenium(II) polypyridyl complexes have drawn growing attention due to their photophysical properties and anticancer activity. Herein we report four ruthenium(II) polypyridyl complexes [(N^N)2RuII(L)]2+ (1-4, L = 4-anilinoquinazoline derivatives, N^N = bidentate ligands with bis-nitrogen donors) as multi-functional anticancer agents. The epidermal growth factor receptor (EGFR) is overexpressed in a broad range of cancer cells and related to many kinds of malignance. EGFR inhibitors, such as gefitinib and erlotinib, have been approved as clinical anticancer drugs. The EGFR-inhibiting 4-anilinoquinazoline ligands greatly enhanced the in vitro anticancer activity of these ruthenium(II) polypyridyl complexes against a series of human cancer cell lines compared to [Ru(bpy)2(phen)], but interestingly, these complexes were actually not potent EGFR inhibitors. Further mechanism studies revealed that upon irradiation with visible light, complexes 3 and 4 generated a high level of singlet oxygen (1O2), and their in vitro anticancer activities against human non-small-cell lung (A549), cervical (HeLa) and squamous (A431) cancer cells were significantly improved. Specifically, complex 3 displayed potent phototoxicity upon irradiation with blue light, of which the photo-toxicity indexes (PIs) against HeLa and A431 cells were 11 and 8.3, respectively. These complexes exhibited strong fluorescence emission at ca. 600 nm upon excitation at about 450 nm. A subcellular distribution study by fluorescence microscopy imaging and secondary ion mass spectrometry imaging (ToF-SIMS) demonstrated that complex 3 mainly localized at the cytoplasm and complex 4 mainly localized in the nuclei of cells. Competitive binding with ctDNA showed that complex 4 was more favorable to bind to the DNA minor groove than complex 3. These differences support that complex 3 possibly exerts its anticancer activities majorly by photo-induced 1O2 generation and complex 4 by binding to DNA. Show less

Title: Comparative studies on Abstract: On the basis of our previous comparative studies on the DNA binding of a pair of ruthenium(II) complex enantiomers, Δ-[Ru(bpy)2PBIP]2+ and Λ-[Ru(bpy)2PBIP]2+ {bpy = 2,2'-bipyridine, PBIP = 2-(4-bromophenyl)imidazo[4,5-f]1,10-phenanthroline}, in this study, their antitumor activities and mechanisms were further investigated comparatively. The cytotoxicity assay demonstrated that both the enantiomers exerted selective antiproliferative effects on cancer cell lines A2780 and PC3. Fluorescence localization experiments suggested that both the enantiomers effectively permeated the nucleus of HeLa cells and co-localized with DNA, resulting in their DNA damage and apoptosis. Flow cytometry experiments showed that the apoptosis was enhanced by increasing the concentration of each enantiomer. Western blotting analyses indicated that both extrinsic and intrinsic apoptosis pathways were activated by the two enantiomers. miRNA microarray analyses displayed that both the enantiomers up- and downregulated multiple miRNAs, some of which were predicted to be associated with carcinogenesis. The above experimental results also showed that the Δ-enantiomer exerted a more potent antitumor activity, a higher efficiency of entering cancer cells and a stronger apoptosis-inducing effect compared with the Λ-enantiomer. Combined with the previously published research results, experimental results from this study implied that the antitumor activity of a metal complex might have originated from the conformation change of DNA in tumor cells caused by the intercalation of the complex, that the antitumor mechanism of a metal complex could be related to its DNA-binding mode, and that the antitumor efficiency of a metal complex could result from its DNA-binding strength. Show less

Selective chemotherapeutic strategies necessitate the emergence of a photosensitive scaffold to abate the nuisance of cancer. In the current context, photo-activated chemotherapy (PACT) has, therefore, appeared to be very effective to vanquish the vehemence of triple-negative breast cancer (TNBC). Metal complexes have been identified to act well against cancer cell microenvironment (high GSH content, low pH, and hypoxia), and thus they have been employed in the treatment of various types of cancer. As TNBC is very challenging to treat owing to its poor prognosis, lack of a specific target, high chance of relapse, and strong metastatic ability, herein we have aspired to design GSH-resistant phototoxic Ru(II)/Ir(III)/Re(I) based pyrene imidazophenathroline complexes to selectively avert the triple-negative breast cancer. The application of complexes, [RuL], [IrL], and [ReL] in the absence and in the presence of GSH against MDA-MB-231TNBC cells, has revealed that they are very active upon irradiation of visible light compared to dark due to the creation of copious singlet oxygen (¹O₂) as reactive oxygen species (ROS). Among three synthesized complexes, [IrL] has shown outstanding potency (IC₅₀ = 3.70 in the absence of GSH and IC₅₀ = 3.90 in the presence of GSH). Also, the complex, [IrL] is capable of interacting with DNA with the highest binding constant (K_b = 0.023 × 10⁶ M^-1) along with higher protein binding affinity (K_BSA = 0.0321 × 10⁶ M^-1). Here, it has been unveiled that all the complexes have been entitled to involve DNA covalent interaction through the available sites of both adenine and guanine bases. Show less

Cellular energy metabolism is reprogrammed in cancer to fuel proliferation. In oncological therapy, treatment resistance remains an obstacle and is frequently linked to metabolic perturbations. Identifying metabolic changes as vulnerabilities opens up novel approaches for the prevention or targeting of acquired therapy resistance. Insights into metabolic alterations underlying ruthenium-based chemotherapy resistance remain widely elusive. In this study, colon cancer HCT116 and pancreatic cancer Capan-1 cells were selected for resistance against the clinically evaluated ruthenium complex sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (BOLD-100). Gene expression profiling identified transcriptional deregulation of carbohydrate metabolism as a response to BOLD-100 and in resistance against the drug. Mechanistically, acquired BOLD-100 resistance is linked to elevated glucose uptake and an increased lysosomal compartment, based on a defect in downstream autophagy execution. Congruently, metabolomics suggested stronger glycolytic activity, in agreement with the distinct hypersensitivity of BOLD-100-resistant cells to 2-deoxy-d-glucose (2-DG). In resistant cells, 2-DG induced stronger metabolic perturbations associated with ER stress induction and cytoplasmic lysosome deregulation. The combination with 2-DG enhanced BOLD-100 activity against HCT116 and Capan-1 cells and reverted acquired BOLD-100 resistance by synergistic cell death induction and autophagy disturbance. This newly identified enhanced glycolytic activity as a metabolic vulnerability in BOLD-100 resistance suggests the targeting of glycolysis as a promising strategy to support BOLD-100 anticancer activity. Show less

The clinical application of photodynamic therapy is hindered by the high glutathione concentration, poor cancer-targeting properties, poor drug loading into delivery systems, and an inefficient activation of the cell death machinery in cancer cells. To overcome these limitations, herein, the formulation of a promising Ir^III complex into a biodegradable coordination polymer (IrS NPs) is presented. The nanoparticles were found to remain stable under physiological conditions but deplete glutathione and disintegrate into the monomeric metal complexes in the tumor microenvironment, causing an enhanced therapeutic effect. The nanoparticles were found to selectively accumulate in the mitochondria where these trigger cell death by hybrid apoptosis and ferroptosis pathways through the photoinduced production of singlet oxygen and superoxide anion radicals. This study presents the first example of a coordination polymer that can efficiently cause cancer cell death by apoptosis and ferroptosis upon irradiation, providing an innovative approach for cancer therapy. Show less

Owing to the safety and low toxicity, photodynamic therapy (PDT) for cancer treatment has received extensive attention. However, the excess H₂S in cancer cells reduces the PDT efficiency, because H₂S indirectly depletes the reactive oxygen species (ROS). To improve anticancer efficiency, a mitochondria-targeted iridium(III) complex Ir-MMB has been developed as H₂S consumer and photo-oxidation anticancer agent. On the one hand, complex Ir-MMB can consume H₂S with sensitive phosphorescence turn-on, which has been successfully applied to exogenous and endogenous H₂S response imaging in living cells. On the other hand, Ir-MMB can enhance its anticancer activity and cause photo-oxidation damage via catalyzing the oxidation of reduced form of nicotinamide-adenine dinucleotide (NADH) to NAD⁺ and producing H₂O₂ under light, and ultimately results in cell apoptosis through mitochondrial depolarization and ROS production. Show less

Quantifying the content of metal-based anticancer drugs within single cancer cells remains a challenge. Here, we used single-cell inductively coupled plasma mass spectrometry to study the uptake and retention of mononuclear (Ir1) and dinuclear (Ir2) Ir^III photoredox catalysts. This method allowed rapid and precise quantification of the drug in individual cancer cells. Importantly, Ir2 showed a significant synergism but not an additive effect for NAD(P)H photocatalytic oxidation. The lysosome-targeting Ir2 showed low dark toxicity in vitro and in vivo. Ir2 exhibited high photocatalytic therapeutic efficiency at 525 nm with an excellent photo-index in vitro and in tumor-bearing mice model. Interestingly, the photocatalytic anticancer profile of the dinuclear Ir2 was much better than the mononuclear Ir1, indicating for the first time that dinuclear metal-based photocatalysts can be applied for photocatalytic anticancer treatment. Show less

To reduce the side effects of marketed cancer drugs against triple negative breast cancer cells we have reported mitochondria targeting half-sandwich iridium(iii)-Cp*-arylimidazophenanthroline complexes for MDA-MB-468 cell therapy and diagnosis. Out of five Ir(iii) complexes (IrL1-IrL5), [iridium(iii)-Cp*-2-(naphthalen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline]PF₆ (IrL1) has exhibited the best cytoselectivity against MDA-MB-468 cells compared to normal HaCaT cells along with excellent binding efficacy with DNA as well as serum albumin. The subcellular localization study of the complex revealed the localization of the compound in cytoplasm thereby pointing to a possible mitochondrial localization and consequent mitochondrial dysfunction via MMP alteration and ROS generation. Moreover, the IrL1 complex facilitated a substantial G₁ phase cell-cycle arrest of MDA-MB-468 cells at the highest tested concentration of 5 μM. The study verdicts support the prospective therapeutic potential of the IrL1 complex in the treatment and eradication of triple negative breast cancer cells. These results validate that these types of scaffolds will be fairly able to exert great potential for tumor diagnosis as well as therapy in the near future. Show less

Ferroptosis is a programmed cell death pathway discovered in recent years, and ferroptosis-inducing agents have great potential as new antitumor candidates. Here, we report a Ir^III complex (Ir1) containing a ferrocene-modified diphosphine ligand that localizes in lysosomes. Under the acidic environments of lysosomes, Ir1 can effectively catalyze Fenton-like reaction, produce hydroxyl radicals, induce lipid peroxidation, down-regulate glutathione peroxidase 4, and result in ferroptosis. RNA sequencing analysis shows that Ir1 can significantly affect pathways related to ferroptosis and cancer immunity. Accordingly, Ir1 can induce immunogenic cells death and suppress tumor growth in vitro, regulate T cell activity and immune microenvironments in vivo. In conclusion, we show the potential of small molecules with ferroptosis-inducing capabilities for effective cancer immunotherapy. Show less

Oncosis (from Greek ónkos, meaning "swelling") is a non-apoptotic cell death process related to energy depletion. In contrast to apoptosis, which is the main form of cell death induced by anticancer drugs, oncosis has been relatively less explored but holds potential to overcome drug resistance phenomena. In this study, we report a novel rationally designed mitochondria-targeted iridium(III) complex (OncoIr3) with advantageous properties as a bioimaging agent. OncoIr3 exhibited potent anticancer activity in vitro against cancer cells and displayed low toxicity to normal dividing cells. Flow cytometry and fluorescence-based assays confirmed an apoptosis-independent mechanism involving energy depletion, mitochondrial dysfunction and cellular swelling that matched with the oncotic process. Furthermore, a Caenorhabditis elegans tumoral model was developed to test this compound in vivo, which allowed us to prove a strong oncosis-derived antitumor activity in animals (with a 41% reduction of tumor area). Indeed, OncoIr3 was non-toxic to the nematodes and extended their mean lifespan by 18%. Altogether, these findings might shed new light on the development of anticancer metallodrugs with non-conventional modes of action such as oncosis, which could be of particular interest for the treatment of apoptosis-resistant cancers. Show less

Glycoconjugation is a powerful tool to improve the anticancer activity of metal complexes. Herein, we modified commercial arylphosphanes with carbohydrate-derived fragments for the preparation of novel glycoconjugated ruthenium(II) p-cymene complexes. Specifically, d-galactal and d-allal-derived vinyl epoxides (VEβ and VEα) were coupled with (2-hydroxyphenyl)diphenylphosphane, affording the 2,3-unsaturated glycophosphanes 1β and 1α. Ligand exchange with [Ru(C₂O₄)(η⁶-p-cymene)(H₂O)] gave the glycoconjugated complexes Ru1β and Ru1α which were subsequently dihydroxylated with OsO₄/N-methylmorpholine N-oxide to Ru2β and Ru2α containing O-benzyl d-mannose and d-gulose units respectively. Besides, aminoethyl tetra-O-acetyl-β-d-glucopyranoside was condensed with borane-protected (4-diphenylphosphanyl)benzoic acid by HATU/DIPEA under MW heating, to afford the amide 3∙BH₃. Zemplén deacylation with MeONa/MeOH gave the deprotected d-glucopyranoside derivative 4∙BH₃. The glycoconjugated phosphane complexes Ru3 and Ru4 were obtained by reaction of the phosphane-boranes 3∙BH₃ and 4∙BH₃ with [Ru(C₂O₄)(η⁶-p-cymene)(H₂O)]. The employed synthetic strategies were devised to circumvent unwanted phosphine oxidation. The compounds were purified by silica chromatography, isolated in high yield and purity and characterized by analytical and spectroscopic (IR and multinuclear NMR) techniques. The behaviour of the six glycoconjugated Ru complexes in aqueous solutions was assessed by NMR and MS measurements. All compounds were screened for their in vitro cytotoxicity against A2780/A2780R human ovarian and MCF7 breast cancer cell lines, revealing a significant cytotoxicity for complexes containing the 2,3-unsaturated glycosyl unit (Ru1β, Ru1α). Additional studies on five other human cancer cells, as well as time-dependent toxicity and cell-uptake analyses on ovarian cancer cells, confirmed the prominent activity of these two compounds - higher than cisplatin - and the better performance of the β anomer. However, Ru1β, Ru1α did not show preferential activity against cancer cells with respect to fetal lung fibroblast and human embryonic kidney cells as models of normal cells. The effects of the two ruthenium glycoconjugated compounds in A2780 ovarian cancer cells were further investigated by cell cycle analysis, induction of apoptosis, intracellular ROS production, activation of caspases 3/7 and disruption of mitochondrial membrane potential. The latter is a relevant factor in the mechanism of action of the highly cytotoxic Ru1β, inducing cell death by apoptosis. Show less

The reaction of [Ru₂Cl₂(μ-Cl)₂(η⁶-p-cymene)₂] with two thiosemicarbazones obtained by the condensation of N-(4-methoxybenzyl) thiosemicarbazide and 1,4-hydroxy-3-methoxyphenyl)ethan-1-one (HL¹) or 2-fluoro-4-hydroxybenzaldehyde (HL²) was studied. The cationic complexes of formula [RuCl(η⁶-p-cymene)(HL)]⁺ were isolated as solid chloride and trifluoromethylsulfate (TfO) salts. A study of the solid state and NMR spectra suggests the presence in the material of two isomers that differ in the configuration in the iminic bond, C2=N3, of the coordinated thiosemicarbazone in the triflate salts and only the E isomer in the chloride. An X-ray study of single crystals of the complexes supports this hypothesis. The thiosemicarbazone ligand coordinates with the ruthenium center through the iminic and sulfur atoms to form a five-membered chelate ring. Furthermore, the isolation of single crystals containing the thiosemicarbazonate complex [Ru₂(μ-L²)₂(η⁶-p-cymene)₂]²⁺ suggests the easy labilization of the coordinated chloride in the complex. The redox behavior of the ligands and complexes was evaluated by cyclic voltammetry. It seems to be more difficult to oxidize the complex derived from HL¹ than HL². The ability of the complexes to inhibit cell growth against the NCI-H460, A549 and MDA-MB-231 lines was evaluated. The complexes did not show greater potency than cisplatin, although they did have greater efficacy, especially for the complex derived from HL¹. Show less

Title: Formation of Iridium(III) and Rhodium(III) Amine, Imine, and Amido Complexes Based on Pyridine-Amine Ligands: Structural Diversity Arising from Reaction Conditions, Substituent Variation, and Metal Centers. Abstract: Herein, we present the different coordination modes of half-sandwich iridium(III) and rhodium(III) complexes based on pyridine-amine ligands. The pyridyl-amine iridium(III) and rhodium(III) complexes, the corresponding oxidation pyridyl-imine products, and 16-electron pyridyl-amido complexes can be obtained through the change in reaction conditions (nitrogen/adventitious oxygen atmosphere, reaction time, and solvents) and structural variations in the metal and ligand. Overall, the reaction of pyridine-amine ligands with [(η5-C5(CH3)5)MCl2]2 (M = Ir or Rh) in the presence of adventitious oxygen afforded the oxidized pyridyl-imine complexes. The possible mechanism for the oxidation of iridium(III) and rhodium(III) amine complexes was confirmed by the detection of the byproduct hydrogen peroxide. Moreover, the formation of pyridyl-amine complexes was favored when nonpolar solvent CH2Cl2 was used instead of CH3OH. The rarely reported complex with [(η5-Cp*)IrCl3] anions can also be obtained without the addition of NH4PF6. The introduction of the sterically bulky i-Bu group on the bridge carbon of the ligand led to the formation of stable 16-electron pyridyl-amido complexes. The pyridyl-amine iridium(III) and rhodium(III) complexes were also synthesized under a N2 atmosphere, and no H2O2 was detected in the whole process. In particular, the aqueous solution stability and in vitro cytotoxicity toward A549 and HeLa human cancer cells of these complexes were also evaluated. No obvious selectivity was observed for cancer cells versus normal cells with these complexes. Notably, the represented complex 5a can promote an increase in the reactive oxygen species level and induce cell death via apoptosis. Show less

By rational altering the structure of CN auxiliary ligand, Near-infrared (NIR) phosphorescent cyclometalated platinum (II) and iridium (III) complexes with metformin (Met) have been successfully obtained and characterized. The dissociation of Met in aqueous solution can be accelerated by addition of Glutathione (GSH) and alleviated by drop of histidine, accompanied with a significant decay change of deep red phosphorescence. Besides, Pt3 and Ir1 with moiety of btpq mainly selectively targeted and located in Mitochondrial, while Pt1 of ppy and Pt2 with thpy mainly accumulated in endoplasmic reticulum. Moreover, Pt1-3 and Ir1 with metformin moiety all exert a significant enhanced anticancer activity, among them, Pt3 displays ca.66-fold, ca.147-fold and ca.588-fold higher cytotoxicity than cisplatin, Met-free analogue Pt3a and Met. Their relative anticancer mechanism was further investigated, both Pt2 and Pt3 could form covalent interaction with bovine serum albumin (BSA) and effectively induce reactive oxygen species (ROS) generation, arrest of cell cycle, loss of Mitochondrial membrane potential (MMP), display effective anti-metastasis activity and eventually induce apoptosis of cancer cell. Show less

In this study, we present the synthesis, kinetic studies of inhibitory activity toward aldo-keto reductase 1C (AKR1C) enzymes, and anticancer potential toward chemoresistant ovarian cancer of 10 organoruthenium compounds bearing diketonate (1-6) and hydroxyquinolinate (7-10) chelating ligands with the general formula [(η⁶-p-cymene)Ru(chel)(X)]ⁿ⁺ where chel represents the chelating ligand and X the chlorido or pta ligand. Our studies show that these compounds are potent inhibitors of the AKR enzymes with an uncommon inhibitory mechanism, where two inhibitor molecules bind to the enzyme in a first fast and reversible step and a second slower and irreversible step. The binding potency of each step is dependent on the chemical structure of the monodentate ligands in the metalloinhibitors with the chlorido complexes generally acting as reversible inhibitors and pta complexes as irreversible inhibitors. Our study also shows that compounds 1-9 have a moderate yet better anti-proliferative and anti-migration action on the chemoresistant ovarian cancer cell line COV362 compared to carboplatin and similar effects to cisplatin. Show less

Phosphrescent complexes of monodentate imidazole have been reported before, but their dissociation induced by cellular endogenous stimulus have never been explored. In our work, the dissociation of monodentate imidazole ligands from phosphorescent cyclometalated platinum (II) iridium (III) and polypyridyl ruthenium (II) complexes in GSH abundant reductive solution are firstly investigated. The release rate of ligand follows the order: Pt (II) > Ir (III) > > Ru (II) in vitro, while their corresponding bidentate complexes are barely affected. Moreover, the cellular dissociation of ligand can be monitored in time by Confocal imaging and flow cytometry. In brief, cellular penetration and nucleolus targeting ability of GSH active complexes are mainly interfered by the reductive microenvironment. Our work may help to reveal the dynamic process of coordination and release of monodentate ligands of complexes in cellular microenvironment. Show less

Ligand HMSPIP (2-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its iridium(III) complexes [Ir(ppy)₂(HMSPIP)]PF₆ (ppy = 2-phenylpyridine, Ir1) and [Ir(bzq)₂(HMSPIP)]PF₆ (bzq = benzo[h]quinoline, Ir2) were synthesized. The complexes were characterized by ¹H NMR, ¹³C NMR, and UV/Vis spectra. The cytotoxicity of the complexes toward cancer cells were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, the scratch wound healing and colony-forming were also investigated. MTT assay certificated that the complexes show high toxic effect on the HeLa cells. The cell cycle assay illustrated that the complexes blocked cell growth at G₀/G₁ phase in HeLa cells. A series of subsequent experiments showed that the complexes first enter the endoplasmic reticulum (ER) and then enter the mitochondria, leading to an increase in intracellular Ca²⁺ and reactive oxygen species (ROS) content, depolarizing mitochondrial membrane potential (MMP), and ultimately resulting in apoptosis. In addition, the experimental results revealed that the complexes not only increase the level of ROS but also inhibit the production of GSH and eventually produce large amounts of MDA and further leading to cell death. Taken together, we consider that the complexes can be used as potential candidate drugs for HeLa cancer treatment. Show less