📚 BiometalDB

Novel ruthenium-letrozole complexes have been prepared, and cell viability of two human cancer cell types (breast and glioblastoma) was determined. Some ruthenium compounds are known for their cytotoxicity to cancer cells, whereas letrozole is an aromatase inhibitor administered after surgery to post-menopausal women with hormonally responsive breast cancer. A significant in vitro activity was established for complex 5·Let against breast cancer MCF-7 cells and significantly lower activity against glioblastoma U251N cells. The activity of 5·Let was even higher than that of 4, a compound analogous to the well-known drug RAPTA-C. Results from the combination of 5·Let (or 4) with 3-methyladenine (3-MA) or with curcumin, respectively, revealed that the resultant cancer cell death likely involves 5·Let-induced autophagy. Show less

The in vitro antiproliferative activity of the title compound on five tumor cell lines shows preference for the colon-rectal tumor HCT116, IC(50) = 13.98 μM, followed by breast MCF7 (19.58 μM) and ovarian A2780 (23.38 μM) cell lines; human glioblastoma U-87 and lung carcinoma A549 are less sensitive. A commercial curcumin reagent, also containing demethoxy and bis-demethoxy curcumin, was used to synthesize the title compound, and so (p-cymene)Ru(demethoxy-curcuminato)chloro was also isolated and chemically characterized. The crystal structure of the title compound shows (1) the chlorine atom linking two neighboring complexes through H-bonds with two O(hydroxyl), forming an infinite two-step network; (2) significant twist in the curcuminato, 20° between the planes of the two phenyl rings. This was also seen in the docking of the Ru-complex onto a rich guanine B-DNA decamer, where a Ru-N7(guanine) interaction is detected. This Ru-N7(guanine) interaction is also seen with ESI-MS on a Ru-complex-guanosine derivative. Show less

The synthesis and full characterization of new half-sandwich ruthenium(II) complexes containing κ(3)(N,N,N)-hydridotris(pyrazolyl)borate (κ(3)(N,N,N)-Tp) and the water-soluble phosphanes 1,3,5-triaza-7-phosphatricyclo[3.3.1.1(3,7)]decane (PTA) and 1-methyl-3,5-diaza-1-azonia-7-phosphatricyclo[3.3.1.1(3,7)]decane (1-CH(3)-PTA) has been explored. Single crystal X-ray diffraction analysis for complex [RuCl{κ(3)(N,N,N)-Tp}(PMe(2)Ph)(1-CH(3)-PTA)][CF(3)SO(3)]·2NCMe is also reported. DNA binding properties of the ruthenium complexes have been evaluated by mobility shift assay and MALDI-TOF mass spectrometry. The in vitro antitumor activity of these compounds was assessed by examining their ability to inhibit cell proliferation in a number of human cancer cell lines (NCI-H460, SF-268, MCF-7) and non-tumor human umbilical vein endothelial cells (HUVEC). Some of these new compounds show promising cytotoxic activity with IC(50) values in the low micromolar range, and display differential effects on cancer and normal cell growth. Show less

Reactions of ω-diphenylphosphino-functionalized alkyl phenyl sulfides Ph(2)P(CH(2))(n)SPh (n=1, L1; 2, L2; 3, L3), sulfoxides Ph(2)P(CH(2))(n)S(O)Ph (n=1, L4; 2, L5; 3, L6) and sulfones Ph(2)P(CH(2))(n)S(O)(2)Ph (n=1, L7; 2, L8; 3, L9) with the dinuclear chlorido bridged ruthenium(II) complex [{Ru(η(6)-p-cymene)Cl(2)}(2)] afforded mononuclear ruthenium(II) complexes of the type [Ru(η(6)-p-cymene)Cl(2){Ph(2)P(CH(2))(n)S(O)(x)Ph-κP}] (n/x=1/0, 1; 2/0, 2; 3/0, 3; 1/1, 4; 2/1, 5; 3/1, 6; 1/2, 7; 2/2, 8; 3/2, 9) having the P(∩)S(O)(x) ligands κP coordinated. The complexes were characterized by (1)H, (13)C and (31)P NMR spectroscopy. The crystal structures of complexes 2, 7·CH(2)Cl(2) and 8 were determined by X-ray diffraction analysis. All complexes have been screened for cytostatic activity against cell lines 518A2, 8505C, A253, MCF-7, and SW480. In vitro biological experiments demonstrate that these compounds are active toward the used cell lines. The ruthenium(II) complex [Ru(η(6)-p-cymene)Cl(2){Ph(2)P(CH(2))(2)SPh-κP}] (2) is the most active compound in the human cancer cell line MCF-7 with the IC(50) value 1.4 μM lower than cisplatin (2.0 μM). Show less

The antitumor activity of the organometallic ruthenium(II)-arene complexes, RuCl(2)(eta(6)-arene)(PTA), (arene = p-cymene, toluene, benzene, benzo-15-crown-5, 1-ethylbenzene-2,3-dimethylimidazolium tetrafluoroborate, ethyl benzoate, hexamethylbenzene; PTA = 1,3,5-triaza-7-phosphaadamantane), abbreviated RAPTA, has been evaluated. In vitro biological experiments demonstrate that these compounds are active toward the TS/A mouse adenocarcinoma cancer cell line whereas cytotoxicity on the HBL-100 human mammary (nontumor) cell line was not observed at concentrations up to 0.3 mM, which indicates selectivity of these ruthenium(II)-arene complexes to cancer cells. Analogues of the RAPTA compounds, in which the PTA ligand is methylated, have also been prepared, and these prove to be cytotoxic toward both cell lines. RAPTA-C and the benzene analogue RAPTA-B were selected for in vivo experiments to evaluate their anticancer and antimetastatic activity. The results show that these complexes can reduce the growth of lung metastases in CBA mice bearing the MCa mammary carcinoma in the absence of a corresponding action at the site of primary tumor growth. Pharmacokinetic studies of RAPTA-C indicate that ruthenium is rapidly lost from the organs and the bloodstream. Show less

The limitations of cisplatin-based chemotherapy, including high toxicity, undesirable side effects, and drug resistance, have motivated extensive investigations into alternative metal-based cancer therapies. Ruthenium (Ru) possesses several favorable properties suited to rational anticancer drug design and biological applications. In the present study, we synthesized a series of ruthenium polypyridyl complexes containing N,N-chelating ligands, examined their anticancer activities, and elucidated the molecular mechanisms through which they caused the cancer cell death. The results demonstrated that [Ru(phen)(2)-p-MOPIP](PF(6))(2).2H(2)O (RuPOP), a complex with potent antiproliferative activity, is able to induce mitochondria-mediated and caspase-dependent apoptosis in human cancer cells. On the basis of these results, we suggest that RuPOP may be a candidate for further evaluation as a chemopreventive and chemotherapeutic agent for human cancers, especially for melanoma. Show less

Third-generation aromatase inhibitors such as anastrozole (ATZ) and letrozole (LTZ) are widely used to treat estrogen receptor-positive ER+ breast cancers in postmenopausal women. Investigating their ability to coordinate metals could lead to the emergence of a new category of anticancer drug candidates with a broader spectrum of pharmacological activities. In this study, a series of ruthenium (II) arene complexes bearing the aromatase inhibitor anastrozole was synthesized and characterized. Among these complexes, [Ru(η ⁶ -C₆H₆)(PPh₃)(η ¹ -ATZ)Cl]BPh₄ (3) was found to be the most stable in cell culture media, to lead to the highest cellular uptake and in vitro cytotoxicity in two ER+ human breast cancer cell lines (MCF7 and T47D), and to induce a decrease in aromatase activity in H295R cells. Exposure of zebrafish embryos to complex 3 (12.5 μM) did not lead to noticeable signs of toxicity over 96 h, making it a suitable candidate for further in vivo investigations. Show less

The special ability of organometallic complexes to catalyze various transformations might offer new effective mechanisms for the treatment of cancer. Studies that report both the biological properties and the ability of metallic complexes to promote therapeutically relevant catalytic reactions are limited. Herein, we report the anticancer activity and catalytic potential of some ruthenium(II)-arene complexes bearing bidentate Schiff base ligands (2a and 2b) and their reduced analogues (5a and 5b, respectively). In comparison to their Schiff base counterparts 2a and 2b, we demonstrate that amine complexes 5a and 5b display (i) a higher in vitro antiproliferative activity on different human cancer cell lines, (ii) a lower rate of hydrolysis, and (iii) an improved initial catalytic rate for the reduction of NAD⁺ to NADH. In contrast to their imine analogues 2a and 2b, we also show that amine complexes 5a and 5b induce the generation of intracellular reactive oxygen species (ROS) in MCF-7 breast cancer cells. Our results highlight the impact that a simple ligand modification such as the reduction of an imine moiety can have on both the catalytic and biological activities of metal complexes. Moreover, the ruthenium complexes reported here display some antiproliferative activity against T47D breast cancer cells, known for their cis-platin resistance. Show less

Ru(II) sulfoxide-maltolato complexes, Ru(ma)(2)(L)(2) (L = DMSO (1a) and TMSO (1b) or L(2) = BESE (1c)), were synthesized, as well as the analogous ethylmaltolato derivatives, Ru(etma)(2)(L)(2) (2a-c) (ma = 3-hydroxy-2-methylpyran-4-onate, etma = 2-ethyl-3-hydroxypyran-4-onate, TMSO = tetramethylene sulfoxide, BESE = 1,2-bis(ethylsulfinyl)ethane). A Ru(II) bidentate sulfoxide-metronidazole complex, RuCl(2)(BESE)(metro)(2) (3), was also synthesized (metro = metronidazole = 2-methyl-5-nitroimidazole-1-ethanol). The complexes were characterized generally by (1)H NMR, UV-vis, and IR spectroscopies, as well as MS, elemental analysis, solution conductivity, and cyclic voltammetry. The molecular structures of Ru(ma)(2)(S,R-BESE) (1c) and trans-RuCl(2)(R,R-BESE)(metro)(2) (3) were determined by X-ray crystallography. All sulfoxide ligands are S-bonded. The complexes were tested against human breast cancer cells (MDA-MB-435S) using an in vitro MTT assay, a colorimetric determination of cell viability: 2a,b exhibit the lowest IC(50) values of 190 +/- 10 and 220 +/- 10 microM, respectively. Cisplatin exhibits an IC(50) value of 30 +/- 5 microM. Show less

New anticancer ruthenium(II/III) complexes [RuCl₂(DMSO)₂(Hapbim)] (1) and [RuCl₃(DMSO) (Hapbim)] (2) (Hapbim = 2-aminophenyl benzimidazole) have been synthesized and characterized, and their chemotherapeutic potential evaluated. The interaction of the compounds with DNA was studied by both UV-Visible and fluorescence spectroscopies, revealing intercalation of both the Hapbim ligand and the Ru complexes. The in vitro cytotoxicity of the compounds was tested on human breast cancer (MCF7), human colorectal cancer (Caco2), and normal human liver cell lines (THLE-2), with compound (2) the most potent against cancer cells. The cytotoxic effect of (2) is shown to correlate with the ability of the Ru(III) complex to induce apoptosis and to cause cell-cycle arrest in the G2/M phase. Notably, both compounds were inactive in the noncancerous cell line. The anticancer effect of (2) has also been studied in an EAC (Ehrlich Ascites Carcinoma) mouse model. Significantly, the activity of the complex was more pronounced in vivo, with removal of the cancer burden at doses that resulted in only low levels of hepatotoxicity and nephrotoxicity. An apoptosis mechanism was determined by the observation of increased Bax and caspase 3 and decreased Bcl2 expression. Furthermore, (2) decreased oxidative stress and increased the levels of antioxidant enzymes, especially SOD, suggesting the enhancement of normal cell repair. Overall, compound (2) shows great potential as a chemotherapeutic candidate, with promising activity and low levels of side effects. Show less

In this study, we newly designed and synthesized a small library of ten structurally related C,N-cyclometalated ruthenium(II) complexes containing various pyridine-functionalized NHC ligand and chelating bipyridyl ligands (e.g., 2,2'-bipyridine, 5,5'-dimethyl-2,2'-bipyridine, and 1,10-phenanthroline (phen)). The complexes were well characterized by NMR, electrospray ionization-mass spectrometry, and single-crystal X-ray structure analyses. Among the new ruthenium(II) derivatives, we identified that the complex Ru8 bearing bulky moieties (i.e., phen and pentamethyl benzene) had the most potent cytotoxicity against all tested cancer cell lines, generating dose- and cell line-dependent IC₅₀ values at the range of 3.3-15.0 μm. More significantly, Ru8 not only efficiently inhibited the metastasis process against invasion and migration of tumor cells but also exhibited potent antivascular effects by suppressing HUVEC cells migration and tube formation in vitro and blocking vessel generation in vivo (chicken chorioallantoic membrane model). In a metastatic A2780 tumor xenograft-bearing mouse model, administration of Ru8 outperformed antimetastatic agent NAMI-A and clinically approved cisplatin in terms of antitumor efficacy and inhibition of metastases to other organs. Overall, these data provided compelling evidence that the new cyclometalated ruthenium complex Ru8 is an attractive agent because of synergistically suppressing bulky tumors and metastasized tumor nudes. Therefore, the complex Ru8 deserves further investigations. Show less

Ru(ii)-polypyridyl complexes have been widely studied and well established for their antitumor properties. Modifications of the coordination environment around the Ru atom through a proper choice of the ligand can lead to different modes of action and result in greatly improved anticancer efficacy. Herein, two Ru(ii)-polypyridyl complexes of curcumin were synthesized and characterized as potential anticancer agents. In vitro tests indicated that complexes 1 and 2 displayed excellent antiproliferative activity against the tested cancer cell lines, especially complex 2, which exhibited superior cytotoxicity compared to curcumin and cisplatin. Further biological evaluations demonstrated that complexes 1 and 2 can cause cell apoptosis via DNA interaction and MEK/ERK signaling pathway, which is the first example of a Ru(ii)-polypyridyl complex inhibiting the MEK/ERK signaling pathway and DNA intercalation. Overall, this work suggests that coordination with bioactive agents may endow Ru(ii)-polypyridyl complexes with improved pharmaceutical properties and synergistic effects for cancer therapy. Show less

Cancer is one of the main causes of death worldwide. Chemotherapy, despite its severe side effects, is to date one of the leading strategies against cancer. Metal-based drugs present several potential advantages when compared to organic compounds and they have gained trust from the scientific community after the approval on the market of the drug cisplatin. Recently, we reported the ruthenium complex ([Ru(DIP)₂ (sq)](PF₆ ) (where DIP is 4,7-diphenyl-1,10-phenantroline and sq is semiquinonate) with a remarkable potential as chemotherapeutic agent against cancer, both in vitro and in vivo. In this work, we analyse a structurally similar compound, namely [Ru(DIP)₂ (mal)](PF₆ ), carrying the flavour-enhancing agent approved by the FDA, maltol (mal). To possess an FDA approved ligand is crucial for a complex, whose mechanism of action might include ligand exchange. Herein, we describe the synthesis and characterisation of [Ru(DIP)₂ (mal)](PF₆ ), its stability in solutions and under conditions that resemble the physiological ones, and its in-depth biological investigation. Cytotoxicity tests on different cell lines in 2D model and on HeLa MultiCellular Tumour Spheroids (MCTS) demonstrated that our compound has higher activity than cisplatin, inspiring further tests. [Ru(DIP)₂ (mal)](PF₆ ) was efficiently internalised by HeLa cells through a passive transport mechanism and severely affected the mitochondrial metabolism. Show less

Inducing necroptosis in cancer cells is an effective approach to circumvent drug-resistance. Metal-based triggers have, however, rarely been reported. Ruthenium(II) complexes containing 1,1-(pyrazin-2-yl)pyreno[4,5-e][1,2,4]triazine were developed with a series of different ancillary ligands (Ru1-7). The combination of the main ligand with bipyridyl and phenylpyridyl ligands endows Ru7 with superior nucleus-targeting properties. As a rare dual catalytic inhibitor, Ru7 effectively inhibits the endogenous activities of topoisomerase (topo) I and II and kills cancer cells by necroptosis. The cell signaling pathway from topo inhibition to necroptosis was elucidated. Furthermore, Ru7 displays significant antitumor activity against drug-resistant cancer cells in vivo. To the best of our knowledge, Ru7 is the first Ru-based necroptosis-inducing chemotherapeutic agent. Show less

Four new transition metal complexes, [M(PPh₃)(L)]^.CH₃OH (M = Ni(II) (1), Pd(II) (2)) [Pt (PPh₃)₂(HL)]Cl (3) and [Ru(CO)(PPh₃)₂(L)] (4) (H₂L = 2,4-dihydroxybenzaldehyde-S-methyldithiocarbazate, PPh₃ = triphenylphosphine) have been synthesized and characterized by elemental analyses (C, H, N), FTIR, NMR (¹H, ³¹P), ESI-MS and UV-visible spectroscopy. The molecular structure of (1) and (2) complexes was confirmed by single-crystal X-ray crystallography. It showed a distorted square planar geometry for both complexes around the metal center, and the H₂L adopt a bi-negative tridentate chelating mode. The interaction with biomolecules viz., calf thymus DNA (ct DNA), yeast RNA (tRNA), and BSA (bovine serum albumin) was examined by both UV-visible and fluorescence spectroscopies. The antioxidant activity of all compounds is discussed on basis of DPPH^• (2,2-diphenyl-1-picrylhydrazyl) scavenging activity and showed better antioxidant activity for complexes compared to the ligand. The in vitro cytotoxicity of the compounds was tested on human (breast cancer (MCF7), colon cancer (HCT116), liver cancer (HepG2), and normal lung fibroblast (WI38)) cell lines, showing that complex (1) the most potent against MCF7 and complex (4) against HCT116 cell lines based on IC₅₀ and selective indices (SI) values. So, both complexes were chosen for further studies such as DNA fragmentation, cell apoptosis, and cell cycle analyses. Complex (1) induced MCF7 cell death by cellular apoptosis and arrest cells at S phase. Complex (4) induced HCT116 cell death predominantly by cellular necrosis and arrested cell division at G2/M phase due to DNA damage. Show less

Four novel monocationic Ru(II) polypyridyl complexes were synthesized with the general formula [Ru(DIP)₂flv]X, where DIP is 4,7-diphenyl-1,10-phenanthroline, flv stands for the flavonoid ligand (5-hydroxyflavone in [Ru(DIP)₂(5-OHF)](PF₆), genistein in [Ru(DIP)₂(gen)](PF₆), chrysin in [Ru(DIP)₂(chr)](OTf), and morin in [Ru(DIP)₂(mor)](OTf)), and X is the counterion, PF₆^-, and OTf ̅ (triflate, CF₃SO₃̅), respectively. Following the chemical characterization of the complexes by ¹H and ¹³C NMR, mass spectrometry, and elemental analysis, their cytotoxicity was tested against several cancer cell lines. The most promising complex, [Ru(DIP)₂(gen)](PF₆), was further investigated for its biological activity. Metabolic studies revealed that this complex severely impaired mitochondrial respiration and glycolysis processes, contrary to its precursor, Ru(DIP)₂Cl₂, which showed a prominent effect only on the mitochondrial respiration. In addition, its preferential accumulation in MDA-MB-435S cells (a human melanoma cell line previously described as mammary gland/breast; derived from metastatic site: pleural effusion), which are used for the study of metastasis, explained the better activity in this cell line compared to MCF-7 (human, ductal carcinoma). 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

In this paper, a series of new ruthenium complexes of the general formula [Ru(NS)(dpphpy)(dppb)]PF₆ (Ru1-Ru3), where dpphpy = diphenyl-2-pyridylphosphine, NS ligands = 2-thiazoline-2-thiol (tzdt, Ru1), 2-mercaptopyrimidine (pySm, Ru2), and 4,6-diamino-2-mercaptopyrimidine (damp, Ru3), and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by elemental analysis, spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and X-ray diffraction. In the characterization, the correlation between the phosphorus atoms and their respective aromatic hydrogen atoms of the compounds in the assignment stands outs, by ¹H-³¹P HMBC experiments. The compounds show anticancer activities against A549 (lung) and MDA-MB-231 (breast) cancer cell lines, higher than the clinical drug cisplatin. All of the complexes are more cytotoxic against the cancer cell lines than against the MRC-5 (lung) and MCF-10A (breast) nontumorigenic human cell lines. For A549 tumor cells, cell cycle analysis upon treatment with Ru2 showed that it inhibits the mitotic phase because arrest was observed in the Sub-G1 phase. Additionally, the compound induces cell death by an apoptotic pathway in a dose-dependent manner, according to annexin V-PE assay. The multitargeted character of the compounds was investigated, and the biomolecules were DNA, topoisomerase IB, and proteasome, as well as the fundamental biomolecule in the pharmacokinetics of drugs, human serum albumin. The experimental results indicate that the complexes do not target DNA in the cells. At low concentrations, the compounds showed the ability to partially inhibit the catalytic activity of topoisomerase IB in the process of relaxation of the DNA plasmid. Among the complexes assayed in cultured cells, complex Ru3 was able to diminish the proteasomal chymotrypsin-like activity to a greater extent. Show less

A series of half-sandwich Ir^III pentamethylcyclopentadienyl and Ru^II arene complexes containing P^P-chelating ligands of the type [(Cp^x/arene)M(P^P)Cl]PF₆, where M = Ir, Cp^x is pentamethylcyclopentadienyl (Cp*), or 1-biphenyl-2,3,4,5-tetramethyl cyclopentadienyl (Cp^xbiPh); M = Ru, arene is 3-phenylpropan-1-ol (bz-PA), 4-phenylbutan-1-ol (bz-BA), or p-cymene (p-cym), and P^P is 2,20-bis(diphenylphosphino)-1,10-binaphthyl (BINAP), have been synthesized and fully characterized, three of them by X-ray crystallography, and their potential as anticancer agents explored. All five complexes showed potent anticancer activity toward HeLa and A549 cancer cells. The introduction of a biphenyl substituent on the Cp* ring for the iridium complexes has no effect on the antiproliferative potency. Ruthenium complex [(η⁶-p-cym)Ru(P^P)Cl]PF₆ (5) displayed the highest potency, about 15 and 7.5 times more active than the clinically used cisplatin against A549 and HeLa cells, respectively. No binding to 9-MeA and 9-EtG nucleobases was observed. Although these types of complexes interact with ctDNA, DNA appears not to be the major target. Compared to iridium complex [(η⁵-Cp*)Ir(P^P)Cl]PF₆ (1), ruthenium complex (5) showed stronger ability to interfere with coenzyme NAD⁺/NADH couple through transfer hydrogenation reactions and to induce ROS in cells, which is consistent with their anticancer activities. The redox properties of the complexes 1, 5, and ligand BINAP were evaluated by cyclic voltammetry. Complexes 1 and 5 arrest cell cycles at the S phase, Sub-G₁ phase and G₁ phase, respectively, and cause cell apoptosis toward A549 cells. Show less

Ruthenium(II) complexes (Ru1-Ru3) with the general formula [Ru(O-O)(PPh₃)₂(bipy)]PF_6, bearing two triphenylphosphine (PPh₃), bipyridine (bipy) and a series of natural and synthetic β-diketones (O,O) ligands were synthesized and characterized using various analytical techniques. The interaction between the complexes and calf thymus DNA (CT-DNA) was investigated and demonstrated a weak interaction. The cytotoxicity of the complexes was investigated against breast cancer cells (MDA-MB-231 and MCF-7), lung cancer cells (A549), cisplatin-resistant ovarian cancer cells (A2780cis), as well as non-tumour lung (MRC-5) and non-tumour breast (MCF-10A) cell lines. All complexes exhibited cytotoxic activity against all the cell lines studied, with half maximal inhibitory concentration (IC₅₀) values ranging from 0.39 to 13 µM. Notably, the three complexes demonstrated selectivity against the A2780cis cell line, with IC₅₀ ranging from 0.39 to 0.82 µM. Among them, Ru2 exhibited the highest cytotoxicity, with an IC₅₀ value of 0.39 µM. Consequently, this new class of complexes shows good selectivity towards cisplatin-resistant ovarian cancer cells and it is promising for further investigation as anti-cancer agents. Show less

Flavonol-metal complexes can enhance the biological activity of flavonols. Inspired by the potential of ruthenium-based drugs in pharmaceutical applications, seven flavonol-Ru (II) complexes were synthesized to evaluate their biological activities. Among these compounds, compounds 8, 11, and 12 showed potent antioxidant activities. Compound 12 exhibited superior anti-inflammatory activity to natural quercetin, which served as a positive control. This study is the first to report the free radical scavenging abilities and antioxidant activity of flavonol-Ru (II) complexes. Furthermore, compound 12 demonstrated comparable efficacy to 5-FU against human non-small-cell lung cancer cells (A549). These results strongly support the potential of flavonol-Ru (II) agents. Show less

Ruthenium complexes bearing bis pyrazole (pzH) ligands, cis-[Ru(bpy)₂(R-pzH)₂]²⁺ (bpy = 2,2'-bipyridine, R = -H, -Cl), were examined as photoactivated anticancer prodrugs. A dicationic pyrazole complex deprotonated to give monocationic pyrazole-pyrazolate complexes, cis-[Ru(bpy)₂(R-pz^-)(R-pzH)]⁺, in an aqueous solution with pK_a values of 9.5 and 7.2 for R = H and R = Cl, respectively. Upon deprotonation, relative quantum yields of photosubstitution decreased while lipophilicity of the complexes increased according to the measurements of water-octanol coefficients. The ruthenium complex with 4-chloropyrazole ligands displayed high cytotoxicity upon light irradiation (IC₅₀ = 0.060 ± 0.016 μM) toward lung cancer cells, which was 7 times higher than that in the dark (IC₅₀ = 0.44 ± 0.07 μM). Additional experiments for the ruthenium R-pyrazole complexes indicated that (1) selective photodissociation of the 4-chloropyrazole ligand occurs from cis-[Ru(bpy)₂(4-Clpz^-)(4-ClpzH)]⁺, (2) photoinduced ligand dissociation is dominant rather than photoinduced generation of singlet oxygen (¹O₂), and (3) induction of cell death occurs via the intrinsic pathway of apoptosis. Show less

Lysosome-targeted photodynamic therapy, which enhances reactive oxygen species (ROS)-responsive tumor cell death, has emerged as a promising strategy for cancer treatment. Herein, a uridine (dU)-modified Ru(II) complex (RdU) was synthesized by click chemistry. It was found that RdU exhibits impressive photo-induced inhibition against the growth of triple-negative breast cancer (TNBC) cells in normoxic and hypoxic microenvironments through ROS production. It was further revealed that RdU induces ferroptosis of MDA-MB-231 cells under light irradiation (650 nm, 300 mW/cm²). Additional experiments showed that RdU binds to lysosomal integral membrane protein 2 (LIMP-2), which was confirmed by the fact that RdU selectively localizes in the lysosomes of MDA-MB-231 cells and significantly augments the levels of LIMP-2. Molecular docking simulations and an isothermal titration calorimetry assay also showed that RdU has a high affinity to LIMP-2. Finally, in vivo studies in tumor-bearing (MDA-MB-231 cells) nude mice showed that RdU exerts promising photodynamic therapeutic effects on TNBC tumors. In summary, the uridine-modified Ru(II) complex has been developed as a potential LIMP-2 targeting agent for TNBC treatment through enhancing ROS production and promoting ferroptosis. Show less

As a basic structure of most polypyridinal metal complexes, [Ru(bpy)₃]²⁺, has the advantages of simple structure, facile synthesis and high yield, which has great potential for scientific research and application. However, sonodynamic therapy (SDT) performance of [Ru(bpy)₃]²⁺ has not been investigated so far. SDT can overcome the tissue-penetration and phototoxicity problems compared to photodynamic therapy. Here, we report that [Ru(bpy)₃]²⁺ is a highly potent sonosensitizer and sonocatalyst for sonotherapy in vitro and in vivo. [Ru(bpy)₃]²⁺ can produce singlet oxygen (¹O₂) and sono-oxidize endogenous 1,4-dihydronicotinamide adenine dinucleotide (NADH) under ultrasound (US) stimulation in cancer cells. Furthermore, [Ru(bpy)₃]²⁺ enables effective destruction of mice tumors, and the therapeutic effect can reach deep tissues over 10 cm under US irradiation. This work paves a way for polypyridinal metal complexes to be applied to the noninvasive precise sonotherapy of cancer. Show less

A series of multichromophoric ruthenium(II) complexes with the formulation [Ru(tpy-BODIPY)(tpy-R)]Cl₂ (1-4), having a heteroleptic Ru(II)-bis-tpy (tpy = 4'-phenyl-2,2':6',2″-terpyridine) moiety covalently linked to a boron-dipyrromethene (BODIPY) pendant, have been prepared and characterized and their application as a phototherapeutic and photodetection agent in cancer therapy has been explored. Ligand L¹ with a terpyridine-BODIPY moiety and complex 1 as its PF₆ salt (1a) have been structurally characterized by a single-crystal X-ray diffraction study. Complex 1a has a distorted-octahedral RuN₆ core with a Ru(II)-bis-terpyridine unit that is covalently linked to one photoactive BODIPY unit. The complexes exhibit strong absorbance near 502 nm (ε ≈ (3.7-7.8) × 10⁴ M^-1 cm^-1) and high singlet oxygen sensitization ability, giving singlet oxygen quantum yield (Φ_Δ) values ranging from 0.57 to 0.75 in DMSO. An emission-based study using complex 4 and Singlet Oxygen Sensor Green (SOSG) displays the formation of singlet oxygen inside the cells and also in the buffer medium upon light irradiation. DNA (pUC19) photocleavage experiments using ROS scavengers/stabilizers reveal photoinduced generation of singlet oxygen by a type-II process and of the superoxide anion radical by a type-I process. Complex 4 having a pendant biotin moiety as a cancer cell targeting group shows high photocytotoxicity with a remarkable phototherapeutic index (PI) value of >1400 in HeLa cancer cells with a low light dose activation (400-700 nm, 2.2 J cm^-2). The complexes display reduced activity in noncancerous HPL1D cells. The emission property of the complexes is used for cellular imaging, thus making them suitable as next-generation theranostic PDT agents. Show less