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It is a major challenge to design novel multifunctional metal-based chemotherapeutic agents for anti-tumor and anti-metastasis applications. Two complexes (OA-Ir and OA-Ru) were synthesized via CuAAC (copper-catalyzed azide-alkyne cycloaddition) reaction from nontoxic Ir-N₃ or Ru-N₃ species and low toxic alkynyl precursor OA-Alkyne, and exhibited satisfactory anti-tumor and anti-metastasis pharmacological effects. Conjugation of Oleanolic acid (OA) and metal-arene species significantly enhanced the cytotoxicity in A2780 cells compared to the precursors through mitochondrial-induced autophagy pathway. Moreover, the two complexes could inhibit the cell metastasis and invasion through damage of actin dynamics and down-regulation of MMP2/MMP9 proteins. Combination of two precursors improved the lipophilicity and biocompatibility, simultaneously enhanced the cell uptake and the mitochondrial accumulation of metal-arene complexes, which caused mitochondrial membrane potential damage, oxidative phosphorylation, ATP depletion and autophagy. Besides, OA-Ir and OA-Ru displayed excellent activity to disintegrate the 3D multicellular tumor spheroids, showing potential for the treatment of solid tumors. This work provides a new way for developing novel metal-based complexes via CuAAC reaction for simultaneously inhibiting tumor proliferation and metastasis. 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

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

Platinum complexes are used in chemotherapy, primarily as antineoplastic agents. In this study, we assessed the cytotoxic and cytostatic properties of a set of osmium(II), ruthenium(II), iridium(III) and rhodium(III) half-sandwich-type complexes with bidentate monosaccharide ligands. We identified 5 compounds with moderate to negligible acute cytotoxicity but with potent long-term cytostatic activity. These structure-activity relationship studies revealed that: (1) osmium(II) p-cymene complexes were active in all models, while rhodium(III) and iridium(III) Cp* complexes proved largely inactive; (2) the biological effect was influenced by the nature of the central azole ring of the ligands-1,2,3-triazole was the most effective, followed by 1,3,4-oxadiazole, while the isomeric 1,2,4-oxadiazole abolished the cytostatic activity; (3) we found a correlation between the hydrophobic character of the complexes and their cytostatic activity: compounds with O-benzoyl protective groups on the carbohydrate moiety were active, compared to O-deprotected ones. The best compound, an osmium(II) complex, had an IC₅₀ value of 0.70 µM. Furthermore, the steepness of the inhibitory curve of the active complexes suggested cooperative binding; cooperative molecules were better inhibitors than non-cooperative ones. The cytostatic activity of the active complexes was abolished by a lipid-soluble antioxidant, vitamin E, suggesting that oxidative stress plays a major role in the biological activity of the complexes. The complexes were active on ovarian cancer, pancreatic adenocarcinoma, osteosarcoma and Hodgkin's lymphoma cells, but were inactive on primary, non-transformed human fibroblasts, indicating their applicability as potential anticancer agents. Show less

A new series of Zr(IV), V(IV), Ru(III), and Cd(II) complexes with the ligand N-((5-hydroxy-4-oxo-4H-pyran-3-yl)methylene)-2-(p-tolylamino)acetohydrazide (H₂L) have been prepared. FT-IR, ¹H-NMR, electronic spectra, powder X-ray, and thermal behavior methods were applied to elucidate the structural composition of new compounds. Geometry optimization for all synthesized compounds was conducted using the Gaussian09 program via the DFT method, to obtain optimal structures and essential parameters. Moreover, the antibacterial and antitumor activity of the ligand and its complexes were studied, where the Cd(II) complex acquires probably the best antibacterial activity followed by the Ru(III) complex towards bacterial species than others when using ampicillin and gentamicin were used as standard drugs. The complexes exhibited interestingly antitumor potential against the MCF-7 breast cancer cell line. The cytotoxicity of the new complexes has been arranged to follow the order: Ru(III) complex > Cd(II) complex > Zr(IV) complex > V(IV) complex > ligand. Molecular docking was performed on the active site of ribosyltransferase and obtained good results. Structure-based molecular docking is used to identify a potential therapeutic inhibitor for NUDT5. Show less

BOLD-100 (sodium trans-[tetrachlorobis(1H indazole)ruthenate(III)]) is a ruthenium-based anticancer compound currently in clinical development. The identification of cancer types that show increased sensitivity towards BOLD-100 can lead to improved developmental strategies. Sensitivity profiling can also identify mechanisms of action that are pertinent for the bioactivity of complex therapeutics. Sensitivity to BOLD-100 was measured in a 319-cancer-cell line panel spanning 24 tissues. BOLD-100's sensitivity profile showed variation across the tissue lineages, including increased response in esophageal, bladder, and hematologic cancers. Multiple cancers, including esophageal, bile duct and colon cancer, had higher relative response to BOLD-100 than to cisplatin. Response to BOLD-100 showed only moderate correlation to anticancer compounds in the Genomics of Drug Sensitivity in Cancer (GDSC) database, as well as no clear theme in bioactivity of correlated hits, suggesting that BOLD-100 may have a differentiated therapeutic profile. The genomic modalities of cancer cell lines were modeled against the BOLD-100 sensitivity profile, which revealed that genes related to ribosomal processes were associated with sensitivity to BOLD-100. Machine learning modeling of the sensitivity profile to BOLD-100 and gene expression data provided moderative predictive value. These findings provide further mechanistic understanding around BOLD-100 and support its development for additional cancer types. Show less

Three iridium (III) polypyridine complexes [Ir(bzq)₂(maip)](PF₆) (Ir1，bzq = benzo[h]quinoline, maip = 3-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(bzq)₂(apip)](PF₆) (Ir2, apip = 2-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(bzq)₂(paip)](PF₆) (Ir3, paip = 4-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized. The cytotoxic activities of the three complexes against human osteosarcoma HOS, U2OS, MG63 and normal LO2 cells were evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method. The results showed that Ir1-3 exhibited moderate antitumor activity against HOS with IC₅₀ of 21.8 ± 0. 4 μM,10.5 ± 1.8 μM and 7.4 ± 0.4 μM, respectively. We found that Ir1-3 can effectively inhibit HOS cells growth and blocked the cell cycle at the G0/G1 phase. Further studies revealed that complexes can increase intracellular reactive oxygen species (ROS) and Ca²⁺, which accompanied by mitochondria-mediated intrinsic apoptosis pathway. In addition, autophagy was also investigated. Taken together, the complexes induce HOS apoptosis through a ROS-mediated mitochondrial dysfunction pathway and inhibition of the PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) signaling pathway. This study provides useful help for understanding the anticancer mechanism of iridium (III) complexes toward osteosarcoma treatment. Show less

Title: Ruthenium(II)-diphosphine complexes containing acylthiourea ligands are effective against lung and breast cancers. Abstract: We have synthesized and characterized three new ruthenium(II) diphosphine complexes containing an acylthiourea ligand, with the general formula [Ru(DPEPhos)(O,S)(bipy)]PF6, where DPEPhos = bis(2-(diphenylphosphino)phenyl)ether, bipy = 2,2'-bipyridine, and O,S = N,N-dimethyl-N'-(benzoyl)thiourea (1), N,N-dimethyl-N'-(furoyl)thiourea (2), and N,N-dimethyl-N'-(thiophenyl)thiourea (3), by several physicochemical techniques. We evaluated the ruthenium complexes for their cytotoxicity against two human cancer cell lines, A549 (lung) and MDA-MB-231 (breast), and two corresponding lines of non-cancer cells, MRC-5 (lung) and MCF-10A (breast). All the complexes are cytotoxic against the cancer cell lines; the IC50 values lie in the micromolar range (0.07-0.70 μM). Ruthenium complex 1 is more selective (7 times more active) toward lung cancer cells (A549) than toward non-cancer cells (MRC-5) and is 160 times more cytotoxic than cisplatin against A549 cells. Investigations of the mechanism of action of complex 1 in A549 cells demonstrated that it inhibits colony formation and promotes cell cycle arrest in the G1 phase and apoptotic cell death. DNA binding studies revealed that complexes 1-3 interact with the biomolecule via minor grooves. These complexes also interact with human serum albumin (HSA) and have affinity for site I by hydrophobic forces. Therefore, this new class of ruthenium complexes can act as cytotoxic agents, mainly for lung cancer treatment. Show less

Title: Fast Hydrolysis and Strongly Basic Water Adducts Lead to Potent Os(II) Half-Sandwich Anticancer Complexes. Abstract: Complexes of the formula [Os(η6-arene)(C,N-phenylpyridine)Z] (where Z is chlorido or a tethered oxygen) undergo very fast Os-Z hydrolysis (<5 min), and the high basicity of the coordinated water molecule of the aqua adducts (Os-OH2; pKa > 8) very much contrasts with previously reported Os-aqua adducts bearing NN- and NO-chelating ligands (pKa < 6). The Os-Cl bond is unreactive in pure DMSO, yet the complexes readily form DMSO adducts upon aquation when dimethyl sulfoxide is present. Such a peculiar aqueous behavior is directly related to the negatively charged CN ligand. Potent Os-CN compounds (but not their Os-NN analogues) are particularly reactive; they bind to cysteine in vitro and decrease the activity of thioredoxin reductase (TrxR) in living cancer cells. By revealing some interesting structure-activity relationship on Os-CN vs Os-NN complexes, we start uncovering the molecular rationale for the successful biological applications of osmium(II) half-sandwich compounds. Show less

Title: Photofunctional cyclometallated iridium(III) polypyridine methylsulfone complexes as sulfhydryl-specific reagents for bioconjugation, bioimaging and photocytotoxic applications. Abstract: We report herein near-infrared (NIR)-emitting cyclometallated iridium(III) complexes bearing a heteroaromatic methylsulfone moiety as sulfhydryl-specific reagents; one of the complexes was conjugated to cysteine and cysteine-containing peptides and proteins for bioimaging and photocytotoxic applications. Show less

Despite the clinical success of photodynamic therapy (PDT), the application of this medical technique is intrinsically limited by the low oxygen concentrations found in cancer tumors, hampering the production of therapeutically necessary singlet oxygen (¹O₂). To overcome this limitation, we report on a novel mitochondria-localized iridium(III) endoperoxide prodrug (2-O-IrAn), which, upon two-photon irradiation in NIR, synergistically releases a highly cytotoxic iridium(III) complex (2-IrAn), singlet oxygen, and an alkoxy radical. 2-O-IrAn was found to be highly (photo-)toxic in hypoxic tumor cells and multicellular tumor spheroids (MCTS) in the nanomolar range. To provide cancer selectivity and improve the pharmacological properties of 2-O-IrAn, it was encapsulated into a biotin-functionalized polymer. The generated nanoparticles were found to nearly fully eradicate the tumor inside a mouse model within a single treatment. This study presents, to the best of our knowledge, the first example of an iridium(III)-based endoperoxide prodrug for synergistic photodynamic therapy/photoactivated chemotherapy, opening up new avenues for the treatment of hypoxic tumors. Show less

Title: Ursolic acid-piperazine-dithiocarbamate ruthenium(II) polypyridyl complexes induced necroptosis in MGC-803 cells. Abstract: Three ursolic acid-piperazine-dithiocarbamate ruthenium(II) polypyridyl complexes Ru1-Ru3 were designed and synthesized for evaluating antitumor activity. All the complexes exhibited high in vitro cytotoxicity against MGC-803, T24, HepG2, CNE2, MDA-MB-231, MCF-7, A549, and A549/DDP cell lines. Ru1, Ru2, and Ru3 were 11, 8 and 10 times, respectively, more active than cisplatin against A549/DDP. An in vivo study on MGC-803 xenograft mouse models demonstrated that representative Ru2 exhibited an effective inhibitory effect on tumor growth, showing stronger antitumor activity than cisplatin. Biological investigations suggested that Ru2 entered MGC-803 cells by a clathrin-mediated endocytic pathway, initially localizing in the lysosomes and subsequently escaping and localizing in the mitochondria. Mitochondrial swelling resulted in vacuolization, which induced vacuolation-associated cell death and necroptosis with the formation of necrosomes (RIP1-RIP3) and the uptake of propidium iodide. These results demonstrate that the potential of Ru2 as a chemotherapeutic agent to kill cancer cells via a dual mechanism represents an alternative way to eradicate apoptosis-resistant forms of cancer. Show less

We have recently reported a series of half-sandwich ruthenium(II) complexes with curcuminoid ligands showing excellent cytotoxic activities (particularly ionic derivatives containing PTA (PTA = 1,3,5-triaza-7-phosphaadamantane). In the present study, new members of this family of compounds have been prepared with the objective to investigate the effect of a long hydrophobic chain obtained by replacing the OH-groups, present in curcumin and bisdemethoxycurcumin, with the palmitic acid ester. We report the synthesis of ruthenium(II) and osmium(II) p-cymene derivatives containing palmitic acid curcumin ester ligands ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(2-methoxy-4,1-phenylene)dipalmitate (p-curcH) and ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(4,1-phenylene)dipalmitate (p-bdcurcH). Complexes [M(II)(cym)(p-curc)/(p-bdcurc)(Cl)] 1-4 (M = Ru or Os) are neutral, whereas [M(II)(cym)(p-curc)/(p-bdcurc)(PTA)][SO₃CF₃] 5-8 are salts obtained when the chloride ligand is replaced by the PTA ligand. Stability studies performed on 1-8 in DMSO-PBS under physiological conditions (pH = 7.4) indicate that the complexes remain intact. The complexes exhibit potent and selective cytotoxic activity against an ovarian carcinoma cell line and its cisplatin-resistant form (A2780 and A2780cis), and non-cancerous human embryonic kidney (HEK293T) cells. To define the structure-activity relationships (SAR), the compounds have been compared with other Ru(II) and Os(II) complexes with curcuminoid ligands previously reported. SAR data reveal that the bisdemethoxycurcumin complexes are generally more active and selective than analogous curcumin-containing complexes. Show less

Cancer is one of the main causes of death worldwide. Platinum complexes (i. e., cisplatin, carboplatin, and others) are currently heavily used for the treatment of different types of cancer, but unwanted effects occur. Ruthenium complexes have been shown to be potential promising alternatives to these metal-based drugs. In this work, we performed a structure-activity relationship (SAR) study on two small series of Ru(II) polypyridyl complexes of the type [Ru(L1)₂ (O^O)]Cl_n (3-8), where L1 is 4,7-diphenyl-1,10-phenantroline (DIP) or 1,10-phenantroline (phen), and O^O is a symmetrical anionic dioxo ligand: oxalate (ox, n=0), malonate (mal, n=0), or acetylacetonate (acac, n=1). These two self-consistent series of compounds allowed us to perform a systematic investigation for establishing how the nature of the ligands and the charge affect the anticancer properties of the complexes. Cytotoxicity tests on different cell lines demonstrated that some of the six compounds 3-8 have a promising anticancer activity. More specifically, the cationic complex [Ru(DIP)₂ (η² -acac)]Cl (4) has IC₅₀ values in the mid-nanomolar concentration range, lower than those of cisplatin on the same cell lines. Interestingly, [Ru(DIP)₂ (η² -acac)]Cl was found to localize mainly in the mitochondria, whereas a smaller fraction was detected in the nucleus. Overall, our SAR investigation demonstrates the importance of combining the positive charge of the complex with the highly lipophilic diimine ligand DIP. 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

Targeting multiple malignancy features such as angiogenesis, proliferation and metastasis with one molecule is an effective strategy in developing potent anticancer agents. Ruthenium metal complexation to bioactive scaffolds is reported to enhance their biological activities. Herein, we evaluate the impact of Ru chelation on the pharmacological activities of two bioactive flavones (1 and 2) as anticancer candidates. The novel Ru complexes (1Ru and 2Ru) caused a loss of their parent molecules' antiangiogenic activities in an endothelial cell tube formation assay. 1Ru enhanced the antiproliferative and antimigratory activities of its 4-oxoflavone 1 on MCF-7 breast cancer cells (IC₅₀ = 66.15 ± 5 μM and 50% migration inhibition, p < 0.01 at 1 μM). 2Ru diminished 4-thioflavone's (2) cytotoxic activity on MCF-7 and MDA-MB-231 yet significantly enhanced 2's migration inhibition (p < 0.05) particularly on the MDA-MB-231 cell line. The test derivatives also showed non-intercalative interaction with VEGF and c-myc i-motif DNA sequences. Show less

Title: Lysosome-targeted cyclometalated iridium(III) complexes: JMJD inhibition, dual induction of apoptosis, and autophagy. Abstract: A series of cyclometalated iridium(III) complexes with the formula [Ir(C^N)2 L](PF6) (C^N = 2-phenylpyridine (ppy, in Ir-1), 2-(2-thienyl)pyridine (thpy, in Ir-2), 2-(2,4-difluorophenyl)pyridine (dfppy, in Ir-3), L = 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)quinolin-8-ol) were designed and synthesized, which utilize 8-hydroxyquinoline derivative as N^N ligands to chelate the cofactor Fe2+ of the Jumonji domain-containing protein (JMJD) histone demethylase. As expected, the results of UV/Vis titration analysis confirm the chelating capabilities of Ir-1-3 for Fe2+, and molecular docking studies also show that Ir-1-3 can interact with the active pocket of JMJD protein, and treatment of cells with Ir-1-3 results in significant upregulation of trimethylated histone 3 lysine 9 (H3K9Me3), indicating the inhibition of JMJD activity. Meanwhile, Ir-1-3 exhibit much higher cytotoxicity against the tested tumor cell lines compared with the clinical chemotherapeutic agent cisplatin. And Ir-1-3 can block the cell cycle at the G2/M phase and inhibit cell migration and colony formation. Further studies show that Ir-1-3 can specifically accumulate in lysosomes, damage the integrity of lysosomes, and induce apoptosis and autophagy. Reduction of mitochondrial membrane potential and elevation of reactive oxygen species also contribute to the antitumor effects of Ir-1-3. Finally, Ir-1 can inhibit tumor growth effectively in vivo and increase the expression of H3K9Me3 in tumor tissues. Our study demonstrates that these iridium(III) complexes are promising anticancer agents with multiple functions, including the inhibition of JMJD and induction of apoptosis and autophagy. Show less

Colorectal cancer (CRC) is one of the most common malignancies and one of the leading causes of cancer-related death worldwide, urging the need for new and more efficient therapeutic approaches. Ruthenium complexes have emerged as attractive alternatives to traditional platinum-based compounds in the treatment of CRC. This work aims to evaluate anti-CRC properties, as well as to identify the mechanisms of action of ruthenium complexes with the general formula [Ru(η⁵-C₅H₄R)(PPh₃)(4,4'-R'-2,2'-bipyridine)][CF₃SO₃], where R = CH₃, CHO or CH₂OH and R' = H, CH₃, CH₂OH, or dibiotin ester. The complexes (Ru 1-7) displayed high bioactivity, as shown by low IC₅₀ concentrations against CRC cells, namely, RKO and SW480. Four of the most promising ruthenium complexes (Ru 2, 5-7) were phenotypically characterized and were shown to inhibit cell viability by decreasing cell proliferation, inducing cell cycle arrest, and increasing apoptosis. These findings were in accordance with the inhibition of MEK/ERK and PI3K/AKT signaling pathways. Ruthenium complexes also led to a decrease in cellular clonogenic ability and cell migration, which was associated with the disruption of F-actin cytoskeleton integrity. Here, we demonstrated that ruthenium complexes, especially Ru7, have a high anticancer effect against CRC cells and are promising drugs to be used as a new therapeutical strategy for CRC treatment. Show less