📚 BiometalDB

We report the synthesis and characterization of four neutral organometallic tethered complexes, [Ru(η⁶-Ph(CH₂)₃-ethylenediamine-N-R)Cl], where R = methanesulfonyl (Ms, 1), toluenesulfonyl (Ts, 2), 4-trifluoromethylbenzenesulfonyl (Tf, 3), and 4-nitrobenzenesulfonyl (Nb, 4), including their X-ray crystal structures. These complexes exhibit moderate antiproliferative activity toward human ovarian, lung, hepatocellular, and breast cancer cell lines. Complex 2 in particular exhibits a low cross-resistance with cisplatin. The complexes show potent catalytic activity in the transfer hydrogenation of NAD⁺ to NADH with formate as hydride donor in aqueous solution (310 K, pH 7). Substituents on the chelated ligand decreased the turnover frequency in the order Nb > Tf > Ts > Ms. An enhancement of antiproliferative activity (up to 22%) was observed on coadministration with nontoxic concentrations of sodium formate (0.5-2 mM). Complex 2 binds to nucleobase guanine (9-EtG), but DNA appears not to be the target, as little binding to calf thymus DNA or bacterial plasmid DNA was observed. In addition, complex 2 reacts rapidly with glutathione (GSH), which might hamper transfer hydrogenation reactions in cells. Complex 2 induced a dose-dependent G₁ cell cycle arrest after 24 h exposure in A2780 human ovarian cancer cells while promoting an increase in reactive oxygen species (ROS), which is likely to contribute to its antiproliferative activity. Show less

Current anticancer drug discovery efforts focus on the identification of first-in-class compounds with a mode-of-action distinct from conventional DNA-targeting agents for chemotherapy. An emerging trend is the identification of endoplasmic reticulum (ER) targeting compounds that induce ER stress in cancer cells, leading to cell death. However, a limited pool of such compounds has been identified to date, and there are limited studies done on such compounds to allow for the rational design of ER stress-inducing agents. In our present study, we present a series of highly cytotoxic, ER stress-inducing Ru(II)-arene Schiff-Base (RAS) complexes, bearing iminoquinoline chelate ligands. We demonstrate that by structural modification to the iminoquinoline ligand, we could tune its π-acidity and influence reactive oxygen species (ROS) induction, switching between a ROS-mediated ER stress pathway activation and one that is not mediated by ROS induction. Our current study adds to the available ER stress inducers and shows how structural tuning could be used as a means to modulate the mode-of-action of such compounds. Show less

Our study demonstrates that four novel kinetically inert C,N-cyclometalated Ru^II complexes of the type [Ru(C^N)(N^N)₂ ][PF₆ ] containing a handle for functionalization on the C^N ligand are very potent cytotoxic agents against several different human cancer cell lines and are up to 400-fold more potent than clinically used cisplatin. In addition, the investigated ruthenium complexes are less cytotoxic in noncancerous cells, and exhibit higher selectivity for cancer cells than conventional platinum anticancer drugs. The high potency of the investigated ruthenium compounds can be attributed to several factors, including enhanced internalization and their capability to change mitochondrial transmembrane potential in cells. The new ruthenium complexes also interfere with protein synthesis with a markedly higher potency than conventional inhibitors of DNA translation. Notably, the latter mechanism has not been hitherto described for other cytotoxic Ru compounds and cisplatin. Show less

Drug resistance to existing anticancer agents is a growing clinical concern, with many first line treatments showing poor efficacy in treatment plans of some cancers. Resistance to platinum agents, such as cisplatin, is particularly prevalent in the treatment of ovarian cancer, one of the most common cancers amongst women in the developing world. Therefore, there is an urgent need to develop next generation of anticancer agents which can overcome resistance to existing therapies. We report a new series of organoruthenium(II) complexes bearing structurally modified pyrithione ligands with extended aromatic scaffold, which overcome platinum and adriamycin resistance in human ovarian cancer cells. The mechanism of action of such complexes appears to be unique from that of cisplatin, involving G₁ cell cycle arrest without generation of cellular ROS, as is typically associated with similar ruthenium complexes. The complexes inhibit the enzyme thioredoxin reductase (TrxR) in a model system and reduce cell motility towards wound healing. Importantly, this work highlights further development in our understanding of the multi-targeting mechanism of action exhibited by transition metal complexes. Show less

[RuCl(3).nH(2)O] and Na(trans-[RuCl(4)(DMSO)(2)]) were reacted with 1-pyrrolidinedithiocarbamate (PDT), its S-methyl ester (PDTM), and N,N-dimethylcarbamodithioic acid methyl ester (DMDTM) in water or methanol in order to obtain the corresponding Ru(III) derivatives. Once isolated and purified, the complexes were characterized by means of elemental analysis, conductivity measurements, FT-IR and (1)H NMR spectroscopy, ion electrospray mass spectrometry (ESI-MS), and thermal analyses. The crystal structure of mer-[Ru(DMDTM)(DMSO)Cl(3)] has been also determined by X-ray crystallography. In vitro cytotoxic activity of all the synthesized complexes was eventually evaluated on some selected human tumor cell lines. Show less

The Ru(ii) complex of an imidazole-mesalazine Schiff base is a unique example showing growth inhibition of 3D-colon cancer stem cell spheroids and bulk colon cancer cells at lower dosage than salinomycin or oxaliplatin. Unlike oxaliplatin which increases the expression of stemness genes (SOX2, KLF4, HES1 and Oct4), these complexes maintain a tight regulation. Show less

Bioenergetic therapy targeting mitochondrial bioenergy is a promising therapeutic strategy for cancer. However, its clinical efficacy is limited by the metabolic adaptability of tumor cells, as they can switch between glycolytic and oxidative phosphorylation metabolic phenotypes to maintain energy homeostasis. In this study, we discovered 1,8-naphthyridine-piperazine-dithiocarbamate ruthenium(II) polypyridyl complexes (RuL1) that enhanced energy deprivation by inhibiting the activity of mitochondrial complex I and III, thereby disrupting oxidative phosphorylation. Simultaneously, RuL1 inhibits glycolysis while unexpectedly activating antitumor immunity. This dual metabolic-immunological targeting resulted in enhanced anticancer activity against MGC-803 cells. To the best of our knowledge, RuL1 is the first ruthenium polypyridyl complex reported to achieve high anticancer activity through dual metabolic inhibition. Show less

Title: Ruthenium(II) and copper(II) polyamine complexes as promising antitumor agents: synthesis, characterization, and biological evaluation. Abstract: Ruthenium or copper complexes have emerged as some of the most promising alternatives for the treatment of many types of cancer. They have enhanced activity, greater selectivity and reduced side effects compared to their predecessors, cisplatin and its analogues. On the other hand, polyamine metabolism is often deregulated in cancer, leading to increased intracellular concentrations of polyamines that promote cell proliferation, differentiation, and tumorigenesis. In the present work, we report the synthesis and characterization of a family of mono- and binuclear Ru(II) and Cu(II) complexes functionalized with polyamine ligands derived from norspermine. The computer-aided analysis of the electron paramagnetic resonance (EPR) spectra provided magnetic and dynamic parameters, which helped to identify prevalent Cu-N2 coordination in a partially distorted square planar geometry of the Cu(II) complexes and the flexibility of the complexes in solution, slowed down by both the complex size and the hydrophobic interactions between chains. In vitro studies focused on advanced prostate cancer have demonstrated that these new metal complexes present a high level of cytotoxicity against PC3 cells. Furthermore, these metallic compounds exhibit the ability to inhibit cell adhesion and migration while reducing intracellular reactive oxygen species levels, which are key factors of metastasis. Show less

Pt^II complexes are commonly used to treat cancer. To reduce their side effects and improve their pharmacological properties, Pt^IV complexes are being developed as prodrug candidates that are activated by reduction in cancer cells. Concomitantly, Ru^II polypyridine complexes have gained much attention as photosensitizers for use in photodynamic therapy due to their attractive characteristics. In this article, a novel Pt^IV -Ru^II conjugate, which combines cancer activated chemotherapy with PDT, is presented. Upon entering the cancer cell, the Pt^IV centre is reduced to Pt^II and the axial ligands including the Ru^II complex and phenylbutyrate are released. As each component has its individual targets, the conjugate exerts a multi-target and multi-action effect with (photo-)cytotoxicity values upon irradiation up to 595 nm in the low nanomolar range in various (drug resistant) 2D monolayer cancer cells and 3D multicellular tumour spheroids. Show less

Ru(II)(η(6)-arene) complexes, especially with bioactive ligands, are considered to be very promising compounds for anticancer drug design. We have shown recently that Ru(II)(η(6)-p-cymene) complexes with 3-hydroxyflavone ligands exhibit very high in vitro cytotoxic activities correlating with a strong inhibition of topoisomerase IIα. In order to expand our knowledge about the structure-activity relationships and to determine the impact of lipophilicity of the arene ligand and of the hydrolysis rate on anticancer activity, a series of novel 3-hydroxyflavone derived Ru(II)(η(6)-arene) complexes were synthesised. Furthermore, the impact of the heteroatom in the bioactive ligand backbone was studied by comparing the cytotoxic activity of Ru(II)(η(6)-p-cymene) complexes of 3-hydroxyquinolinone ligands with that of their 3-hydroxyflavone analogues. To better understand the behaviour of these Ru(II) complexes in aqueous solution, the stability constants and pK(a) values for complexes and the corresponding ligands were determined. Furthermore, the interaction with the DNA model 5'-GMP and with a series of amino acids was studied in order to identify potential biological target structures. Show less

The synthesis, characterization, reactivity and in vitro anticancer activity of a series of Ru(II)-arene complexes with carbohydrate-derived phosphite and biscarboxylato co-ligands are reported. The compounds were characterized by NMR spectroscopy and electrospray ionization (ESI) mass spectrometry, and the molecular structures of oxalato(η(6)-p-cymene)(3,5,6-bicyclophosphite-1,2-O-isopropylidene-α-D-glucofuranoside)ruthenium(II) and oxalato(η(6)-p-cymene)(3,5,6-bicyclophosphite-1,2-O-cyclohexylidene-α-D-glucofuranoside)ruthenium(II) were determined by X-ray diffraction analysis. In contrast to their dichlorido counterparts, the biscarboxylato complexes did not exhibit significant reactivity towards biomolecules, such as cysteine, methionine, ubiquitin or the DNA model 5'-GMP, and resist hydrolysis; no hydrolytic species were detected by (1)H and (31)P{(1)H} NMR spectroscopy over several days. These structural alterations led to a decrease in the tumor-inhibiting potency of the compounds in human cancer cell lines. Show less

The preparation, structural characterization, and chemical behavior in aqueous solution of a series of new Ru[9]aneS3 half-sandwich complexes of the type [Ru([9]aneS3)Cl(NN)][CF3SO3] and [Ru([9]aneS3)(dmso-S)(N-N)][CF3SO3]2 (5-15, NN=substituted bpy or 2x1-methylimidazole) are described. The X-ray structures of [Ru([9]aneS3)Cl(3,3'-H2dcbpy)][CF3SO3] (9) (3,3'-H2dcbpy=3,3'-dicarboxy-2,2'-bipyridine), [Ru([9]aneS3)Cl(4,4'-dmobpy)][CF3SO3] (13) (4,4'-dmobpy=4,4'-dimethoxy-2,2'-bipyridine), and [Ru([9]aneS3)Cl(1-MeIm)2][CF3SO3] (15) (1-MeIm=1-methylimidazole) were also determined. The new compounds are structurally similar to anticancer-active organometallic half-sandwich complexes of formula [Ru(eta6-arene)Cl(NN)][PF6]. Three chloro compounds (5, 9, 15) were tested in vitro for cytotoxic activity against two human cancer cell lines in comparison with the previously described [Ru([9]aneS3)Cl(en)][CF3SO3] (1, en=ethylenediamine), [Ru([9]aneS3)Cl(bpy)][CF3SO3] (2), and with their common dmso precursor [Ru([9]aneS3)Cl(dmso-S)2][CF3SO3] (3). Only the ethylenediamine complex 1 showed some antiproliferative activity, ca. one order of magnitude lower than the reference organometallic half-sandwich compound RM175 that contains biphenyl instead of [9]aneS3. This compound was further tested against a panel of human cancer cell lines (including one resistant to cisplatin). Show less

The effect of steric hindrance on reactivity towards biomolecules while designing Ru(II)-η(6)-p-cymene based anticancer agents seems to be an important parameter in improving the activity and inducing resistance against glutathione (GSH) deactivation. Herein we present the structure, hydrolysis, anticancer activity and the effect of steric hindrance on deactivation by glutathione for three complexes, [Ru(II)(η(6)-p-cym)(L1)(Cl)](PF6) (1), [Ru(II)(η(6)-p-cym)(L2)(Cl)](PF6) (2) and [Ru(II)(η(6)-p-cym)(L3)(Cl)](PF6) (3). The ligands L1-L3 are Schiff bases which show increasing substitution in a benzene ring, such that two ortho hydrogens are replaced by -methyl in 2 and by -isopropyl in 3. The cytotoxicity results strongly suggest that controlling the rate of hydrolysis through tuning of steric hindrance may be a feasible pathway to derive GSH resistant anticancer agents. The cellular studies show that all the three complexes show good blood compatibility (haemolysis <3%) and induce cellular death through caspase activation via the mitochondrial pathway. They have anti-angiogenic activity and prevent the healing of treated cells. Show less

A series of neutral pseudo-octahedral RuII sulfonamidoethylenediamine complexes [(η6-p-cym)Ru(N,N')Cl] where N,N' is N-(2-(R1,R2-amino)ethyl)-4-toluenesulfonamide (TsEn(R1,R2)) R1,R2 = Me,H (1); Me,Me (2); Et,H (3); benzyl,H (Bz, 4); 4-fluorobenzyl,H (4-F-Bz, 5) or naphthalen-2-ylmethyl,H (Naph, 6), were synthesised and characterised including the X-ray crystal structure of 3. These complexes catalyse the reduction of NAD+ regioselectively to 1,4-NADH by using formate as the hydride source. The catalytic efficiency depends markedly on the steric and electronic effects of the N-substitutent, with turnover frequencies (TOFs) increasing in the order: 1 < 2 < 3, 6 < 4, 5, achieving a TOF of 7.7 h-1 for 4 with a 95% yield of 1,4-NADH. The reduction rate was highest between pH* (deuterated solvent) 6 and 7.5 and improved with an increase in formate concentration (TOF of 18.8 h-1, 140 mM formate). The calculations suggested initial substitution of an aqua ligand by formate, followed by hydride transfer to RuII and then to NAD+, and indicated specific interactions between the aqua complex and both NAD+ and NADH, the former allowing a preorganisation involving interaction between the aqua ligand, formate anion and the pyridine ring of NAD+. The complexes exhibited antiproliferative activity towards A2780 human ovarian cancer cells with IC50 values ranging from 1 to 31 μM, the most potent complex, [(η6-p-cym)Ru(TsEn(Bz,H))Cl] (4, IC50 = 1.0 ± 0.1 μM), having a potency similar to the anticancer drug cisplatin. Co-administration with sodium formate (2 mM), increased the potency of all complexes towards A2780 cells by 20-36%, with the greatest effect seen for complex 6. Show less

The investigation of the hydrogen-bonding effect on the aggregation tendency of ruthenium compounds [(η⁶-p-cymene)Ru(κNHR,κNOH)Cl]Cl (R = Ph (1a), Bn (1b)) and [(η⁶-p-cymene)Ru(κ²NH(2-pic),κNOH)][PF₆]₂ (1c), [(η⁶-p-cymene)Ru(κNHBn,κNO)Cl] (2b) and [(η⁶-p-cymene)Ru(κNBn,κ²NO)] (3b), has been performed by means of concentration dependence ¹H NMR chemical shifts and DOSY experiments. The synthesis and full characterization of new compounds 1c, [(η⁶-p-cymene)Ru(κNPh,κ²NO)] (3a) and 3b are also reported. The effect of the water soluble ruthenium complexes 1a-1c on cytotoxicity, cell adhesion and cell migration of the androgen-independent prostate cancer PC3 cells have been assessed by MTT, adhesion to type-I-collagen and recovery of monolayer wounds assays, respectively. Interactions of 1a-1c with DNA and human serum albumin have also been studied. Altogether, the properties reported herein suggest that ruthenium compounds 1a-1c have considerable potential as anticancer agents against advanced prostate cancer. 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

Antibiotic resistance is a global problem, and one promising solution to overcome this issue is using metallodrugs, which are drugs containing metal ions and ligands. These complexes are superior to free ligands in various characteristics including anticancer properties and mechanism of action. The pharmacological potential of metallodrugs can be modulated by the appropriate selection of ligands and metal ions. A good example of proper coordination is the combination of sulfonamides (sulfamerazine, sulfathiazole) with a ruthenium(III) ion. This work aimed to confirm that the activity of sulfonamides antibacterial drugs is initiated and/or stimulated by their coordination to an Ru(III) ion. The study determined the structure, electrochemical profile, CT-DNA affinity, and antimicrobial as well as anticancer properties of the synthesized complexes. The results proved that Ru(III) complexes exhibited better biological properties than the free ligands. Show less

Title: Unraveling Mechanism and Enhancing Selectivity of a Ru Abstract: The Warburg effect, which generates increased demand of glucose in cancer cells is a relatively underexplored phenomenon in existing commercial drugs to enhance uptake in cancer cells. Here, we present a chemotherapeutic strategy employing a Ru(II)-bis-bipyridyl-morphocumin complex (2) encapsulated in a self-assembling glucose-functionalized copolymer P(G-EMA-co-MMA) (where G=glucose; MMA=methyl methacrylate; EMA=ethyl methacrylate), designed to exploit this effect for enhanced selectivity in cancer treatment. The P(G-EMA-co-MMA) polymer, synthesized via reversible-addition fragmentation chain transfer (RAFT) polymerization, has a number average molecular weight (Mn,NMR) of 8000 g/mol. Complex 2, stable in aqueous media, selectively releases a cytotoxic, lysosome-targeting compound, morphocumin, in the presence of excess hydrogen peroxide (H₂O₂), a reactive oxygen species (ROS) prevalent in tumor microenvironments. Additionally, complex 2 promotes ROS accumulation, which may further enhance morphocumin release through a synergistic domino effect. Comparative studies reveal that 2 outperforms its curcumin Ru(II) complex (1) analog in solution stability, organelle specificity, and cellular mechanisms. Both 1 and 2 exhibit phototherapeutic effects under low-intensity visible light, but their chemotoxicity significantly increases with incubation time in the dark, highlighting the superior chemotherapeutic efficacy of the O,O-coordinating Ru(II) ternary polypyridyl complexes. Complex 2 induces apoptosis via the intrinsic pathway and shows a 9-fold increase in selectivity for pancreatic cancer cells (MIA PaCa-2) over non-cancerous HEK293 cells when encapsulated in the glucose-conjugated polymer (DP@2). Glucose deprivation in the culture medium further enhances drug efficacy by an additional 5-fold. This work underscores the potential of glucose-functionalized polymers and ROS-responsive Ru(II) complexes in targeted cancer therapy. Show less

A series of novel octahedral ruthenium(III) complexes involving 6-benzylaminopurine (L) derivatives as N-donor ligands has been prepared by the reaction of [(DMSO)(2)H][trans-RuCl(4)(DMSO)(2)] with the corresponding L derivative. The complexes 1-12 have the general compositions trans-[RuCl(4)(DMSO)(n-Cl-LH)]⋅xSol (1-3), trans-[RuCl(4)(DMSO)(n-Br-LH)]·xSol (4-6), trans-[RuCl(4)(DMSO)(n-OMe-LH)]·xSol (7-9) and trans-[RuCl(4)(DMSO)(n-OH-LH)]·xSol (10-12); n=2, 3, and 4, x=0-1.5; and Sol = H(2)O, DMSO, EtOH and/or (Me)(2)CO. The complexes have been thoroughly characterized by elemental analysis, UV-visible, FTIR, Raman, and EPR spectroscopy, ES+(positive ionization electrospray) mass spectrometry, thermal analysis, cyclic voltammetry, magnetic and conductivity measurements. The X-ray molecular structure of trans-[RuCl(4)(DMSO)(3-Br-LH)]⋅(Me)(2)CO (5) revealed the distorted octahedral coordination in the vicinity of the central atom, and also confirmed that the 3-Br-L ligand is present as the N3-protonated N7-H tautomer and is coordinated to Ru(III) through the N9 atom of the purine moiety. The tested complexes have been found to be in vitro non-cytotoxic against K562, G361, HOS and MCF7 human cancer cell lines with IC(50)>100μM in contrast to the moderate results regarding the antiradical activity with IC(50)≈10(-3)M. On the contrary, in vivo antitumor activity screening showed that the prepared Ru(III) complexes possess higher pro-apoptotic activity than NAMI-A. The reduction of Ru(III) to Ru(II) and Ru(II)-species formation in tumor tissues was confirmed by means of a simple method of detection and visualization of intracellular Ru(II) by fluorescence microscopy. The originality of this method is based on the preparation of a Ru(II)-bipyridine complex in situ. Show less