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The curative effect of sorafenib in hepatocellular carcinoma (HCC) is limited and sorafenib resistance remains a major obstacle for HCC. To overcome this obstacle, a new photoactive sorafenib-Ru(II) complex Ru-Sora has been designed. Upon irradiation (λ = 465 nm), Ru-Sora rapidly releases sorafenib and generates reactive oxygen species, which can oxidize intracellular substances such as GSH. Cellular experiments show that irradiated Ru-Sora is highly cytotoxic toward Hep-G2 cells, including sorafenib-resistant Hep-G2-SR cells. Compared to sorafenib, Ru-Sora has a significant photoactivated chemotherapeutic effect against Hep-G2-SR cancer cells and 3D Hep-G2 multicellular tumor spheroids. Furthermore, Ru-Sora inducing apoptosis and ferroptosis is proved by GSH depletion, GPX4 downregulation, and lipid peroxide accumulation. Metabolomics results suggest that Ru-Sora exerts photocytotoxicity by disrupting the purine metabolism, which is expected to inhibit tumor development. This study provides a promising strategy for enhancing chemotherapy and combating drug-resistant HCC disease. Show less

Title: Exploring the in vitro anticancer activities of Re(I) picolinic acid and its fluorinated complex derivatives on lung cancer cells: a structural study. Abstract: Fifteen rhenium(I) tricarbonyl complexes of the form fac-[Re(N,O')(CO)3(X)], where N,O'-bidentate ligand = 2-picolinic acid (Pico); 3,5-difluoropyridine-2-carboxylic acid (Dfpc); 3-trifluoromethyl-pyridine-2-carboxylic acid (Tfpc) and X = H2O; pyrazole (Pz); pyridine (Py); imidazole (Im); and methanol (CH3OH) were synthesized using the '2 + 1' mixed ligand approach with an average yield of 84%. The complexes were characterized using the following spectroscopic techniques: IR, 1H and 13C NMR, UV/Vis, and single-crystal X-ray diffraction. The effect of the fluorine atoms on the backbone of the N,O'-bidentate ligand was investigated and a trend was noticed in the carbonyl stretching frequencies: with Pico < Tfpc < Dfpc. The in vitro biological screening on Vero (healthy mammalian), HeLa (cervical carcinoma) and A549 (lung cancer) cells revealed one toxic complex, fac-[Re(Pico)(CO)3(H2O)], with respective LC50 values of 9.0 ± 0.9, 15.8 ± 4.9 (SI = 0.570) and 20.9 ± 0.8 (SI = 0.430) μg/mL. As a result, it can be used as a positive control drug of toxicity. Show less

Ruthenium(II) complexes of the type [Ru(bpy)₂(L¹/L²/L³)]PF₆ [where bpy = 2,2'-bipyridine, H(L¹) = N-(pyrid-2-yl)salicylaldimine (1), H(L²) = N-(6-methylpyrid-2-yl)salicylaldimine (2), and H(L³) = N-(4,6-dimethylpyrid-2-yl)salicylaldimine (3)] have been isolated. The X-ray structures of 1-3 reveal distorted octahedral coordination geometry with a planar ruthenium phenolate moiety. They exhibit interpair dimeric association in their solid state such as (a) π-π-stacking interactions (1-3) and (b) C-H···π interactions (2). The ¹H NMR spectral data shed light on the characteristics of metal-ligand bonding and chelate ring conformations. The complexes exhibit strong metal-to-ligand charge-transfer transitions in the visible region. The complexes also undergo two successive metal-based oxidative processes corresponding to the Ru^II/Ru^III and Ru^III/Ru^IV couples. Resonance Raman studies strongly suggest that the lowest unoccupied molecular orbital of 1-3 is localized at the bpy ligand. Absorption, emission, and circular dichroic spectral measurements for 1-3 with calf-thymus DNA reveal a groove binding mode of interaction. Interestingly, all of the complexes exhibit pH-dependent DNA damage, and the pH at which the damage is highest corresponds to the pH conditions of the cancer cells. The DNA damage is in the order of 3 > 2 > 1, in which a hydrolytic mechanism dominates. The protein binding properties of the complexes examined by the tryptophan quenching measurements suggest a static mechanism. The positive ΔH and ΔS values indicate that the force acting between the complexes and bovine serum albumin (BSA) is mainly a hydrophobic interaction, and thus BSA may act as a targeted drug-delivery vehicle for ruthenium(II) complexes (K ∼ 10⁵). It is noteworthy that 3 exhibits selectivity with high cytotoxicity against breast cancer cells (EVSA-T and MCF-7), and its potency is comparable to that of cisplatin. Show less

Complexes of Ru(III), Pt(IV), and Au(III) with sulfamethoxazole (SMX) were experimentally produced. The resulted formations of novel metal complexes were discussed using several techniques, such as effective magnetic moment molar conductivity, IR, UV, and 1H NMR spectra, elemental analyses, thermal analysis, microscopic and XRD analyses. The X-ray diffraction patterns of the solid powders of the synthesized sulfamethoxazole complexes indicated their identical formulation. The surface uniformity of the complexes’ samples was confirmed by SEM images. These complexes appear as spots, dark in appearance, with particle sizes of 100–200 nanometers in transmission electron microscopy (TEM) pictures. The sulfamethoxazole ligand was shown to be bidentate coordinated to the metallic ions with sulfonyle oxygen and amido nitrogen groups, according to IR spectral data. Both Ru(III) and Au(III) complexes have an electrolytic nature, but the Pt(IV) complex has non-electrolytic properties. TG and DTG experiments proved the assigned composition and provided information regarding the thermal stability of complexes in a dynamic air atmosphere, according to the thermal analysis. The effect of the novel prepared complexes was examined for antibacterial and antifungal activity in vitro against a variety of pathogens, and they exceeded the sulfamethoxazole ligand in antibacterial activity. It was observed that the Pt(IV) complex has the ultimate activity versus all the assessed organisms relative to all compounds. 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

New mononuclear and dinuclear Ru(II) coordination compounds with the 2,7-bisbenzoimidazolyl-naphthyridine ligand have been synthesized and characterized by UV-vis, NMR, and MALDI-TOF. The molecular structures for Ru(II) compounds were determined by single-crystal X-ray diffraction. With the expansion of ligand π-conjugation and the increase in the complexed Ru number, the maximum emission wavelength red-shifted from 696 to 786 nm. The binding mode between complexes and DNA was predicted by molecular docking, which is intercalations and π-π stacking interactions with the surrounding bases. The intercalation mode of DNA binding was then determined by DNA titration and ethidium bromide (EB) displacement experiments. The antigrowth effects of complexes RuY, RuY1, and RuY2 were tested in HaCat (normal cells), HeLa (cervical cancer), A549 (lung cancer), and A549/DDP (cisplatin-resistant lung cancer) through the MTT assay. The dinuclear complex RuY2 was superior to mononuclear complexes and cisplatin in the cisplatin-resistant cell line. Confocal imaging proved that the subcellular localization of Ru(II) complexes was mitochondria; moreover, apoptosis was detected by flow cytometry. All three complexes showed a dose-dependent manner in all four cell lines. All Ru(II) complexes were found to have reactive oxygen species (ROS). The finding indicated that these Ru(II) complexes caused cell death by both DNA disruption and ROS. This study helps to explore the potential of the polynuclear Ru(II) complexes for the combination of NIR imaging and Pt-resistant cancer therapy. Show less

Title: Anticancer ruthenium(II) tris(pyrazolyl)methane complexes with bioactive co-ligands. Abstract: In comparison with RuII-arene compounds, the medicinal potential of homologous RuII-tpm compounds [tpm = tris(pyrazolyl)methane] is underexplored. Pyridine, 4-pyridinemethanol and four functionalized pyridines, synthesized from the esterification of 4-pyridinemethanol with bioactive carboxylic acids (i.e., ethacrynic acid, ibuprofen, flurbiprofen and naproxen), react with the precursor [RuCl(κ3-tpm)(PPh3)2]Cl (1) to afford [RuCl(κ3-tpm)(PPh3)(L)]Cl (2-7, L = pyridine ligand), in 78-91% yields. All products were fully characterized by HR-ESI mass spectrometry, IR and multinuclear NMR spectroscopy and the solid-state structures of two of the complexes, i.e. where L = pyridine and 4-pyridinemethanol, were ascertained by single crystal X-ray diffraction. The {Ru-tpm-PPh3} assembly is stable in D2O and in biological medium (DMEM) at 37 °C, with a tendency to slowly dissociate the pyridine ligand. The antiproliferative activity of the complexes was assessed on the cancerous A2780 and A2780cisR cell lines, and the nontumoral HEK 293T cell line; moreover inhibition assays were carried out on the complexes towards COX-2 and GSTP1 enzymes. Show less

The synthesis, characterisation, and evaluation of the in vitro cytotoxicity of five maleonitriledithiolate-based ruthenium metal complexes bearing various phosphine ligands towards two ovarian cancer cell lines (A2780 and A2780cisR), one non-small-cell lung cancer cell line (H460) and one normal prostate cell line (PNT2) are presented herein. These 18-electron complexes were designed with four water-soluble phosphine ligands to increase the water-solubility character of the corresponding electron-deficient ruthenium complex which showed great in vitro promises, and triphenylphosphine for comparison. The complexes with triphenylphosphine-3,3',3''-trisulfonic acid and triphenylphosphine present similar cytotoxicity compared to the 16-electron precursor, with equal cytotoxicity to both A2780 and A2780cisR. Hints at the mechanism of action suggest an apoptotic pathway based on reactive oxygen species (ROS) production. No toxicity was observed in preliminary in vivo pilot studies for these two complexes in subcutaneous A2780 and A2780cisR xenograft models, with some evidence of tumour growth delay. Show less

We disclose novel amphiphilic ruthenium and osmium complexes that auto-assemble into nanomedicines with potent antiproliferative activity by inhibition of mitochondrial respiration. The self-assembling units were rationally designed from the [M(p-cymene)(1,10-phenanthroline)Cl]PF₆ motif (where M is either Ru^II or Os^II) with an appended C₁₆ fatty chain to achieve high cellular activity, nano-assembling and mitochondrial targeting. These amphiphilic complexes block cell proliferation at the sub-micromolar range and are particularly potent towards glioblastoma neurospheres made from patient-derived cancer stem cells. A subcutaneous mouse model using these glioblastoma stem cells highlights one of our C₁₆ Os^II nanomedicines as highly successful in vivo. Mechanistically, we show that they act as metabolic poisons, strongly impairing mitochondrial respiration, corroborated by morphological changes and damage to the mitochondria. A genetic strategy based on RNAi gave further insight on the potential involvement of microtubules as part of the induced cell death. In parallel, we examined the structural properties of these new amphiphilic metal-based constructs, their reactivity and mechanism. Show less

Two novel phosphine ligands, Ph₂PCH₂N(CH₂CH₃)₃ (1) and Ph₂PCH₂N(CH₂CH₂CH₂CH₃)₂ (2), and six new metal (Cu(I), Ir(III) and Ru(II)) complexes with those ligands: iridium(III) complexes: Ir(η5-Cp*)Cl₂(1) (1a), Ir(η5-Cp*)Cl₂(2) (2a) (Cp*: Pentamethylcyclopentadienyl); ruthenium(II) complexes: Ru(η6-p-cymene)Cl₂(1) (1b), Ru(η6-p-cymene)Cl₂(2) (2b) and copper(I) complexes: [Cu(CH₃CN)₂(1)BF₄] (1c), [Cu(CH₃CN)₂(2)BF₄] (2c) were synthesized and characterized using elemental analysis, NMR spectroscopy, and ESI-MS spectrometry. Copper(I) complexes turned out to be highly unstable in the presence of atmospheric oxygen in contrast to ruthenium(II) and iridium(III) complexes. The studied Ru(II) and Ir(III) complexes exhibited promising cytotoxicity towards cancer cells in vitro with IC₅₀ values significantly lower than that of the reference drug-cisplatin. Confocal microscopy analysis showed that Ru(II) and Ir(III) complexes effectively accumulate inside A549 cells with localization in cytoplasm and nuclei. A precise cytometric analysis provided clear evidence for the predominance of apoptosis in induced cell death. Furthermore, the complexes presumably induce the changes in the cell cycle leading to G2/M phase arrest in a dose-dependent manner. Gel electrophoresis experiments revealed that Ru(II) and Ir(III) inorganic compounds showed their unusual low genotoxicity towards plasmid DNA. Additionally, metal complexes were able to generate reactive oxygen species as a result of redox processes, proved by gel electrophoresis and cyclic voltamperometry. In vitro cytotoxicity assays were also carried out within multicellular tumor spheroids and efficient anticancer action on these 3D assemblies was demonstrated. It was proven that the hydrocarbon chain elongation of the phosphine ligand coordinated to the metal ions does not influence the cytotoxic effect of resulting complexes in contrast to metal ions type. Show less

Targeted therapy showed broad application prospects in the treatment of various types of cancer. Through carriers such as aptamers, antibodies, proteins and peptides, targeted therapy can selectively deliver drugs into tumor cells. Compared with traditional treatment methods such as chemo- and radiotherapy, targeted drug delivery systems can reduce the toxic effects of drugs on normal cells and avoid adverse reactions. Herein, an aptamer-cyclometalated iridium(III) complex conjugate (ApIrC) has been designed and developed as a targeted anticancer agent. Owing to the targeting ability of aptamers, ApIrC specifically bound to nucleolin over-expressed on the surface of cancer cells and showed strong fluorescence signal for tumor imaging and diagnosis. ApIrC had more substantial cellular uptake in cancer cells than the iridium complex alone and exhibited favorable low toxicity to normal cells. After uptake by cells through endocytosis, ApIrC can selectively accumulated in mitochondria and induced caspase-3/7-dependent cell death. Remarkably, ApIrC can also specifically target 3D multicellular spheroids (MCSs) and show excellent tumor permeability. So, it can effectively reach the interior of MCSs and cause cell damage. To our knowledge, this is the first report of the aptamer-cyclometalated iridium(III) complex conjugate which studied for cancer targeted therapy. The developed conjugate has great potential to be developed as novel therapeutics for effective and low-toxic cancer treatment. Show less

Targeting metabolic reprogramming to treat cancer could increase overall survival and reduce side effects. Here, we put forward a strategy using arene-ruthenium(II)/osmium(II) complexes to potentiate the anticancer effect of metformin (Met.) via glucose metabolism reprogramming. Complexes 1-6 with oxoglaucine derivatives as ligands were synthesized and their anti-tumor activities were tested under hypoglycemia. Results indicated that 2 and 5 potentiated the anticancer effects of Met. under hypoglycemia, exhibiting lower toxicity, slower blood glucose decline and inhibition of early tumor liver metastasis. Combination of 5 with Met. could be used as a new strategy to treat cancer under hypoglycemia through glucose metabolism reprogramming. Show less

In this paper, two new iridium (III) complexes, [Ir(ppy)2(ipbp)](PF6) (Ir1) (ppy = 2-phenylpyridine, ipbp = 3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2yl)-4H-chromen-4-one) and [Ir(bzq)2(ipbp)](PF6) (Ir2) (bzq = benzo[h]quinolone), were synthesized and characterized. The cytotoxicity of the complexes against human colon cancer HCT116 and normal LO2 cells was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The complexes Ir1 and Ir2 show high cytotoxic efficacy toward HCT116 cells with a low IC50 value of 1.75 ± 0.10 and 6.12 ± 0.2 µM. Interestingly, Ir1 only kills cancer cells, not normal LO2 cells (IC50 > 200 µM). The inhibition of cell proliferation and migration were investigated by multiple tumor spheroid (3D) and wound healing experiments. The cellular uptake was explored under a fluorescence microscope. The intracellular reactive oxygen species (ROS), change of mitochondrial membrane potential, glutathione (GSH) and adenine nucleoside triphosphate (ATP) were studied. Apoptosis and cell cycle arrest were performed by flow cytometry. The results show that the complexes induce early apoptosis and inhibit the cell proliferation at the G0/G1 phase. Additionally, the apoptotic mechanism was researched by Western blot analysis. The results obtained demonstrate that the complexes cause apoptosis in HCT116 cells through ROS-mediated mitochondrial dysfunction and the inhibition of PI3K/AKT signaling pathways. Show less

The quest to find new inhibitors of biologically relevant targets is considered an important strategy to introduce new drug candidates for the treatment of neurodegenerative diseases. A series of (aminomethyl)benzylphosphonates 8a-c and their metallocarbonyl iron 9a-c and ruthenium 10a-c complexes were designed, synthesized, and evaluated for their inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by determination of IC₅₀. Metallocarbonyl derivatives, in general, did not show significant inhibition activity against these enzymes, the most potent inhibitor was the (aminomethyl)benzylphosphonate 8a (IC₅₀ = 1.215 µM against AChE). Molecular docking analysis of AChE and (aminomethyl)benzylphosphonates 8a-c showed the strongest interactions of 8a and AChE compared to isomers 8b and 8c. Cytotoxicity studies of synthesized compounds towards the V79 cell line were also performed and discussed. Show less

Bioactive and luminescent cyclometallated Ir(III) complexes [Ir(ppy)₂ L1]Cl (1) and [Ir(ppy)₂ L2]Cl (2) containing a benzimidazole derivative (L1/L2) as auxiliary mimic of a nucleotide have been synthesised. The emissive properties of both complexes are conditioned by the nature of L1 and L2, rendering an orange and a green emitter respectively. Both are highly emissive with quantum yield increasing in absence of oxygen up to 0.26 (1) and 0.36 (2), suggesting their phosphorescent character. Antiproliferative activity against lung cancer A549 cells increased up to 15 times upon irradiation conditions, reaching IC₅₀ values in the nanomolar range (0.3±0.09 μM (1) and 0.26±0.14 μM (2)) and pointing them as good PSs candidates for photodynamic therapy via ¹ O₂ generation. Cellular biodistribution analysis by fluorescence microscopy suggest the lysosomes as the preferential accumulation organelle. Time-resolved studies showed a greatly increased cellular emission lifetime compared to the solution values, indicating binding to macromolecules or cellular structures and restriction of collision and vibrational quenching. Show less

Photoactivated chemotherapy (PACT) has emerged as a promising strategy to selectively target cancer cells by using light irradiation to generate cytotoxic complexes in situ through a mechanism involving ligand-loss. Due to their rich optical properties and excited state chemistry, Ru polypyridyl complexes have attracted significant attention for PACT. However, studying PACT is complicated by the fact that many of these Ru complexes can also undergo excited-state electron transfer to generate ¹O₂ species. In order to deconvolute the biological roles of possible photo-decomposition products without the added complication of excited-state electron transfer chemistry, we have developed a methodology to systematically investigate each product individually, and assess the structure-function relationship. Here, we synthesized a series of eight distinct Ru polypyridyl complexes: Ru-Xa ([Ru(NN)₃]²⁺), Ru-Xb ([Ru(NN)₂py₂]²⁺), and Ru-Xc ([Ru(NN)(OH₂)₂]²⁺) where NN = 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, or dimethyl 2,2'-bipyridine-4,4'-dicarboxylate and py = pyridine. The cytotoxicity of these complexes was investigated in two cell lines amenable to PACT: H23 (breast cancer) and T47D (lung cancer). We confirmed that light irradiation of Ru-Xa and Ru-Xb complexes generate Ru-Xc complexes through UV-visible spectroscopy, and observed that the Ru-Xc complexes are the most toxic against the cancer cell lines. In addition, we have shown that ligand release and biological activity including bovine serum albumin (BSA) binding, lipophilicity, and DNA interaction are altered when different groups are appended to the bipyridine ligands. We believe that the methodology presented here will enhance the development of more potent and selective PACT agents moving forward. Show less

Title: Cytotoxic properties of rhenium(I) tricarbonyl complexes of N-heterocyclic carbene ligands. Abstract: A family of eight rhenium(I) tricarbonyl complexes bearing pyridyl-imidazolylidene or bis-imidazolylidene ligands in combination with a series of N-acetyl amino acids ligands (glycine, isoleucine, and proline) and an acetate have been synthesised and characterised. These complexes are of interest as potential anticancer agents, where the oxygen bound carboxylate ligand can exchange with water giving rise to cytotoxic cationic complexes. The pseudo-first-order aquation rate constants for the complexes were evaluated using 1H NMR time-course experiments and for the complexes of the bis-imidazolylidene ligand the average k1 value was 6.22 × 10-5 s-1 while for the pyridyl-imidazolylidene ligand the aquation rate was slower with the average k1 value being 3.00 × 10-5 s-1. Cytotoxicity studies in three cancer cell lines (MDA-MB-231, PC3 and HEPG2) showed that the Re(I) complexes of the bis-imidazolylidene ligand were significantly more toxic than those of the pyridyl-imidazolylidene ligand. Show less

Emergence of resistance in cancer cells and dose-limiting side effects severely limit the widespread use of platinum (Pt) anticancer drugs. Multi-action hybrid anticancer agents that are constructed by merging two or more pharmacophores offer the prospect of circumventing issues of Pt drugs. Herein, we report the design, synthesis, and in-depth biological evaluation of a ruthenium-ferrocene (Ru-Fc) bimetallic agent [(η⁶-p-cymene)Ru(1,1,1-trifluoro-4-oxo-4-ferrocenyl-but-2-en-2-olate)Cl] and its five analogues. Along with aquation/anation chemistry, we evaluated the in vitro antitumor potency, Pt cross-resistance profile, and in vivo antiangiogenic properties. A structure activity analysis was performed to understand the impact of Fc, CF₃, and p-cymene groups on the anticancer potency of the Ru-Fc hybrid. Finally, in addition to assessing cellular uptake and intracellular distribution, we demonstrated that the Ru-Fc hybrid binds to nucleophilic biomolecules and produces reactive oxygen species, which causes mitochondrial dysfunction and induces ER stress, leading to poly(ADP-ribose) polymerase-mediated necroptotic cell death. Show less

The dual functionality of 1,2,4,5-tetrazine as a bioorthogonal reactive unit and a luminescence quencher has shaped tetrazine-based probes as attractive candidates for luminogenic labeling of biomolecules in living systems. In this work, three cyclometalated iridium(III) complexes featuring two tetrazine units were synthesized and characterized. Upon photoexcitation, the complexes were non-emissive but displayed up to 3900-fold emission enhancement upon the inverse electron-demand Diels-Alder (IEDDA) [4+2] cycloaddition with (1R,8S,9s)-bicyclo[6.1.0]non-4-yne (BCN) substrates. The rapid reaction kinetics (k₂ up to 1.47×10⁴  M^-1  s^-1 ) of the complexes toward BCN substrates allowed effective peptide labeling. The complexes were also applied as live cell bioimaging reagents and photocytotoxic agents. One of the complexes was utilized in the preparation of luminescent nanosized hydrogels that exhibited interesting cargo delivery properties. Show less

Ruthenium(II) arene complexes exhibit promising chemotherapeutic properties. In this study, the effect of the counter anion in Ru(II) complexes was evaluated by analyzing the biological effect of two Ru(II) p-cymene derivatives with the 1,10-phenanthroline-5,6-dione ligand of general-formula [(η⁶-arene)Ru(L)Cl][X] X = CF₃SO₃ (JHOR10) and PF₆ (JHOR11). The biological activity of JHOR10 and JHOR11 was examined in the ovarian carcinoma cell line A2780, colorectal carcinoma cell line HCT116, doxorubicin-resistant HCT116 (HCT116-Dox) and in normal human dermal fibroblasts. Both complexes JHOR10 and JHOR11 displayed an antiproliferative effect on A2780 and HCT116 cell lines, and low cytotoxicity in fibroblasts. Interestingly, JHOR11 also showed antiproliferative activity in the HCT116-Dox cancer cell line, while JHOR10 was inactive. Studies in A2780 cells showed that JHOR11 induced the production of reactive oxygen species (ROS) that trigger autophagy and cellular senescence, but no apoptosis induction. Further analysis showed that JHOR11 presented no tumorigenicity, with no effect in the cellular mobility, as evaluated by thye wound scratch assay, and no anti- or pro-angiogenic effect, as evaluated by the ex-ovo chorioallantoic membrane (CAM) assay. Importantly, JHOR11 presented no toxicity in chicken and zebrafish embryos and reduced in vivo the proliferation of HCT116 injected into zebrafish embryos. These results show that these are suitable complexes for clinical applications with improved tumor cell cytotoxicity and low toxicity, and that counter-anion alteration might be a viable clinical strategy for improving chemotherapy outcomes in multidrug-resistant (MDR) tumors. 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

While ruthenium arene complexes have been widely investigated for their medicinal potential, studies on homologous compounds containing a tridentate tris(1-pyrazolyl)methane ligand are almost absent in the literature. Ruthenium(II) complex 1 was obtained by a modified reported procedure; then, the reactions with a series of organic molecules (L) in boiling alcohol afforded novel complexes 2-9 in 77-99% yields. Products 2-9 were fully structurally characterized. They are appreciably soluble in water, where they undergo partial chloride/water exchange. The antiproliferative activity was determined using a panel of human cancer cell lines and a noncancerous one, evidencing promising potency of 1, 7, and 8 and significant selectivity toward cancer cells. The tested compounds effectively accumulate in cancer cells, and mitochondria represent a significant target of biological action. Most notably, data provide convincing evidence that the mechanism of biological action is mediated by the inhibiting of mitochondrial calcium intake. Show less