📚 BiometalDB

Title: Rational design of a lysosome-targeting and near-infrared absorbing Ru(ii)-BODIPY conjugate for photodynamic therapy. Abstract: A Ru(ii)-BODIPY conjugate has been rationally designed and exhibits an intense absorption in the NIR region to boost lysosome-targeted PDT in vitro and in vivo. The advantages of Ru(ii) and BODIPY were successfully instilled into the conjugate to yield highly effective PDT efficacy against malignant melanoma A375 cells (PI = 3448) and A375 mice xenografts. Show less

Triple negative breast cancer (TNBC) is a heterogeneous subtype of breast tumors that does not exhibit the expression of estrogen and progesterone receptors, neither the amplification of the human epidermal growth factor receptor 2 (HER-2) gene. Despite all the advances in cancer treatments, the development of new anticancer drugs for TNBC tumors is still a challenge. There is an increasing interest in new agents to be used in cancer treatment. Ruthenium is a metal that has unique characteristics and important in vivo and in vitro results achieved for cancer treatment. Thus, in this work, with the aim to develop anticancer drugs, three new ruthenium complexes containing acylthiourea ligands have been synthesized and characterized: trans-[Ru(PPh₃)₂(N,N-dibutyl-N'-benzoylthioureato-k²O,S)(2,2'-bipyridine (bipy))]PF₆(1), trans-[Ru(PPh₃)₂(N,N-dimethyl-N'-thiophenylthioureato-k²O,S)(bipy)]PF₆(2) and trans-[Ru(PPh₃)₂(N,N-dimethyl-N'-benzoylthioureato-k²O,S)(bipy)]PF₆(3). Then, the cytotoxicity of these three new ruthenium complexes was investigated in TNBC MDA-MB-231 and in non-tumor MCF-10A cells. Complex (2) was the most selective complex and was chosen for further studies to verify its effects on cell morphology, adhesion, migration, invasion, induction of apoptosis and DNA damage in vitro, as well as its toxicity and capacity of causing DNA damage in vivo. Complex (2) inhibited proliferation, migration, invasion, adhesion, changed morphology and induced apoptosis, DNA damage and nuclear fragmentation of TNBC cells at lower concentrations compared to non-tumor MCF-10A cells, suggesting an effective action for this complex on tumor cells. Finally, complex (2) did not induce toxicity or caused DNA damage in vivo when low doses were administered to mice. Show less

The toxicity (IC₅₀) of a series of mononuclear ruthenium complexes containing bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (bb_n) as a tetradentate ligand against three eukaryotic cell lines-BHK (baby hamster kidney), Caco-2 (heterogeneous human epithelial colorectal adenocarcinoma) and Hep-G2 (liver carcinoma)-have been determined. The results demonstrate that cis-α-[Ru(Me₄phen)(bb₇)]²⁺ (designated as α-Me₄phen-bb₇, where Me₄phen = 3,4,7,8-tetramethyl-1,10-phenanthroline) showed little toxicity toward the three cell lines, and was considerably less toxic than cis-α-[Ru(phen)(bb₁₂)]²⁺ (α-phen-bb₁₂) and the dinuclear complex [{Ru(phen)₂}₂{μ-bb₁₂}]⁴⁺. Fluorescence spectroscopy was used to study the binding of the ruthenium complexes with human serum albumin (HSA). The binding of α-Me₄phen-bb₇ to the macrocyclic host molecule cucurbit[10]uril (Q[10]) was examined by NMR spectroscopy. Large upfield ¹H NMR chemical shift changes observed for the methylene protons in the bb₇ ligand upon addition of Q[10], coupled with the observation of several intermolecular ROEs in ROESY spectra, indicated that α-Me₄phen-bb₇ bound Q[10] with the bb₇ methylene carbons within the cavity and the metal center positioned outside one of the portals. Simple molecular modeling confirmed the feasibility of the binding model. An α-Me₄phen-bb₇-Q[10] binding constant of 9.9 ± 0.2 × 10⁶ M^-1 was determined by luminescence spectroscopy. Q[10]-encapsulation decreased the toxicity of α-Me₄phen-bb₇ against the three eukaryotic cell lines and increased the binding affinity of the ruthenium complex for HSA. Confocal microscopy experiments indicated that the level of accumulation of α-Me₄phen-7 in BHK cells is not significantly affected by Q[10]-encapsulation. Taken together, the combined results suggest that α-Me₄phen-7 could be a good candidate as a new antimicrobial agent, and Q[10]-encapsulation could be a method to improve the pharmacokinetics of the ruthenium complex. Show less

Title: Asymmetrically Coordinated Heterodimetallic Ir-Ru System: Synthesis, Computational, and Anticancer Aspects. Abstract: Herein, we present an unprecedented formation of a heterodinuclear complex [{(ppy)2IrIII}(μ-phpy){RuII(tpy)}](ClO4)2 {[1](ClO4)2} using terpyridyl/phenylpyridine as ancillary ligands and asymmetric phpy as a bridging ligand. The asymmetric binding mode (N∧N-∩-N∧N∧C-) of the phpy ligand in {[1](ClO4)2} is confirmed by 1H, 13C, 1H-1H correlated spectroscopy (COSY), high-resolution mass spectrum (HRMS), single-crystal X-ray crystallography techniques, and solution conductivity measurements. Theoretical investigation suggests that the highest occupied molecular orbital (HOMO) and the least unoccupied molecular orbital (LUMO) of [1]2+ are located on iridium/ppy and phpy, respectively. The complex displays a broad low energy charge transfer (CT) band within 450-575 nm. The time-dependent density functional theory (TDDFT) analysis suggests this as a mixture of metal-to-ligand charge transfer (MLCT) and ligand-to-ligand charge transfer (LLCT), where both ruthenium, iridium, and ligands are involved. Complex {[1](ClO4)2} exhibits RuIIIrIII/RuIIIIrIII- and RuIIIIrIII/RuIIIIrIV-based oxidative couples at 0.83 and 1.39 V, respectively. The complex shows anticancer activity and selectivity toward human breast cancer cells (IC50; MCF-7: 9.3 ± 1.2 μM, and MDA-MB-231: 8.6 ± 1.2 μM) over normal breast cells (MCF 10A: IC50 ≈ 21 ± 1.3 μM). The Western blot analysis and fluorescence microscopy images suggest that combined apoptosis and autophagy are responsible for cancer cell death. Show less

Herein a new series of organometallic half-sandwich Ru(Ⅱ) complexes bearing aryl-BIAN chelating ligands with various electron-withdrawing and electron-donating substituents have been developed as theranostic agents. All the complexes display much higher anti-proliferative potency than the clinical chemotherapeutic drug cisplatin towards seven cancer cell lines. The anti-proliferative efficacy of these complexes is correlated to their electron-withdrawing ability. Interestingly, complex Ru1 also potently suppresses cancer cell migration in vitro and effectively inhibit tumor growth in vivo in a CT26 colon cancer mouse xenograft model. Mechanisms of action studies display that Ru1 can favorably accumulate in lysosome and exerts anti-cancer potency by inducing a series of events related to lysosomal dysfunction in CT26 cells. Interestingly, inhibition of lysosomal enzymes leads to suppression of cytotoxicity and apoptosis induced by Ru1. Our results elucidate that complex Ru1 can elicit cytotoxicity through lysosome-mediated apoptosis in vitro and suppress tumor growth in vivo. Show less

Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl][CF₃SO₃] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, ¹H and ³¹P{¹H} NMR, UV-vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC₅₀ values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC₅₀ value about 1 order of magnitude higher than any IC₅₀ concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy. Show less

Acute leukemia, a cancer originating in the bone marrow and blood-forming tissues, poses a significant threat to human health. Chemotherapy may cause a range of side effects and further cause greater suffering to the patients. Thus, reducing the toxicity of the drugs for treating leukemia has become a significant challenge. In this study, we developed two non‑platinum anticancer agents, ole-Ru and ole-Ir, by fusing the natural product oleanolic acid as the ligand into two metal (ruthenium and iridium) precursors. Ole-Ru and ole-Ir not only exhibited remarkable selectivity and cytotoxicity against NB4 cells through the apoptosis pathway, but also demonstrated low toxicity towards normal lung fibroblast cells, suggesting their potential for targeted treatment of acute leukemia cells. This work presents a rational design strategy for metal-based anticancer complexes aimed at inhibiting NB4 cells and expanded the scope of metallodrugs used in the treatment of leukemia. Show less

Mononuclear Ru(III) complexes of the type [Ru(LL)Cl2(H2O)] (LL = monobasic tridentate Schiff base anion: (1Z)-N'-(2-{(E)-[1-(2,4-dihydroxyphenyl)ethylidene]amino}ethyl)-N-phenylethanimidamide [DAE], 4-[(1E)-N-{2-[(Z)-(4-hydroxy-3-methoxybenzylidene)amino]ethyl}ethanimidoyl]benzene-1,3-diol [HME], 4-[(1E)-N-{2-[(Z)-(3,4-dimethoxybenzylidene)amino]ethyl}ethanimidoyl]benzene-1,3-diol [MBE], and N-(2-{(E)-[1-(2,4-dihydroxyphenyl)ethylidene]amino}ethyl)benzenecarboximidoyl chloride [DEE]) were synthesized and characterized using the microanalytical, conductivity measurements, electronic spectra, and FTIR spectroscopy. IR spectral studies confirmed that the ligands act as tridentate chelate coordinating the metal ion through the azomethine nitrogen and phenolic oxygen atom. An octahedral geometry has been proposed for all Ru(III)-Schiff base complexes. In vitro anticancer studies of the synthesized complexes against renal cancer cells (TK-10), melanoma cancer cells (UACC-62), and breast cancer cells (MCF-7) was investigated using the Sulforhodamine B assay. [Ru(DAE)Cl2(H2O)] showed the highest activity with IC50 valves of 3.57 ± 1.09, 6.44 ± 0.38, and 9.06 ± 1.18 μM against MCF-7, UACC-62, and TK-10, respectively, order of activity being TK-10 < UACC-62 < MCF-7. The antioxidant activity by DPPH and ABTS inhibition assay was also examined. Scavenging ability of the complexes on DPPH radical can be ranked in the following order: [Ru(DEE)Cl2(H2O)] > [Ru(HME)Cl2(H2O)] > [Ru(DAE)Cl2(H2O)] > [Ru(MBE)Cl2(H2O)]. Show less

The Ru(III) complexes indazolium [trans-RuCl4(1H-indazole)2] (KP1019) and sodium [trans-RuCl4(1H-indazole)2] (NKP-1339) are leading candidates for the next generation of metal-based chemotherapeutics. Trifluoromethyl derivatives of these compounds and their imidazole and pyridine analogues were synthesized to probe the effect of ligand lipophilicity on the pharmacological properties of these types of complexes. Addition of CF3 groups also provided a spectroscopic handle for (19)F NMR studies of ligand exchange processes and protein interactions. The lipophilicities of the CF3-functionalized compounds and their unsubstituted parent complexes were quantified by the shake-flask method to give the distribution coefficient D at pH 7.4 (log D7.4). The solution behavior of the CF3-functionalized complexes was characterized in phosphate-buffered saline (PBS) using (19)F NMR, electron paramagnetic resonance (EPR), and UV-vis spectroscopies. These techniques, along with fluorescence competition experiments, were also used to characterize interactions with human serum albumin (HSA). From these studies it was determined that increased lipophilicity correlates with reduced solubility in PBS but enhancement of noncoordinate interactions with hydrophobic domains of HSA. These protein interactions improve the solubility of the complexes and inhibit the formation of oligomeric species. EPR measurements also demonstrated the formation of HSA-coordinated species with longer incubation. (19)F NMR spectra show that the trifluoromethyl complexes release axial ligands in PBS and in the presence of HSA. In vitro testing showed that the most lipophilic complexes had the greatest cytotoxic activity. Addition of CF3 groups enhances the activity of the indazole complex against A549 nonsmall cell lung carcinoma cells. Furthermore, in the case of the pyridine complexes, the parent compound was inactive against the HT-29 human colon carcinoma cell line but showed strong cytotoxicity with CF3 functionalization. Overall, these studies demonstrate that lipophilicity may be a determining factor in the anticancer activity and pharmacological behavior of these types of Ru(III) complexes. Show less

Ru(II) and Os(II) complexes of 2-pyridinecarbothioamide ligands were introduced as orally administrable anticancer agents (S.M. Meier, M. Hanif, Z. Adhireksan, V. Pichler, M. Novak, E. Jirkovsky, M.A. Jakupec, V.B. Arion, C.A. Davey, B.K. Keppler, C.G. Hartinger, Chem. Sci., 2013, 4, 1837-1846). In order to identify structure-activity relationships, a series of N-phenyl substituted pyridine-2-carbothiamides (PCAs) were obtained by systematically varying the substituents at the phenyl ring. The PCAs were then converted to their corresponding Ru^II(η⁶-p-cymene) complexes and characterized spectroscopically and by X-ray diffraction as well as in terms of stability in water and HCl. The cytotoxic activity of the PCA ligands and their respective organoruthenium compounds was evaluated in a panel of cell lines (HCT116, H460, SiHa and SW480). The lipophilic PCAs 1-4 showed cytotoxicity in the low micromolar range and 6 was the most potent compound of the series with an IC₅₀ value of 1.1μM against HCT116 colon cancer cells. These observations were correlated with calculated octanol/water partition coefficient (clogP) data and quantitative estimated druglikeness. A similar trend as for the PCAs was found in their Ru complexes, where the complexes with more lipophilic ligands proved to be more cytotoxic in all tested cell lines. In general, the PCAs and their organoruthenium derivatives demonstrated excellent drug-likeness and cytotoxicity with IC₅₀ values in the low micromolar range, making them interesting candidates for further development as orally active anticancer agents. Show less

A series of Ru(II) complexes of the type [Ru(5,6-dmp)(2)(diimine)](2+)1-3 and [Ru(tmp)(2)(diimine)](2+)4-6, where 5,6-dmp is 5,6-dimethyl-1,10-phenanthroline, tmp is 3,4,7,8-tetramethyl-1,10-phenanthroline and diimine is dipyrido-[3,2-d:2',3'-f]-quinoxaline (dpq), dipyrido[3,2-a:2',3'-c]phenazine (dppz) and 11,12-dimethyl-dipyrido[3,2-a:2',3'-c]phenazine (11,12-dmdppz), has been isolated and the DNA binding mode of the complexes studied by using emission and circular dichroic (CD) spectral techniques. All the complexes exhibit induced circular dichroism upon binding to calf thymus (CT) DNA and show preferential binding to AT and mixed (d(CGCGATCGCG)(2)) sequences rather than to GC sequences. The complex [Ru(tmp)(2)(dpq)](2+)4 exhibits enhancement in luminescence higher than [Ru(5,6-dmp)(2)(dpq)](2+)1 upon binding to DNA. In contrast, [Ru(5,6-dmp)(2)(dppz)](2+)2 and [Ru(5,6-dmp)(2)(dmdppz)](2+)3 exhibit luminescence enhancement higher than [Ru(tmp)(2)(dppz)](2+)5 and [Ru(tmp)(2)(dmdppz)](2+)6 respectively upon DNA binding, illustrating the importance of hydrophobic forces of interaction in determining the DNA binding affinity. Among the complexes, 4 exhibits the highest enhancement in fluorescence intensity upon binding to the protein bovine serum albumin (BSA). The cytotoxicity of the complexes has been studied by screening them against non-small lung carcinoma (NCI-H460) cell line. It is noteworthy that the complex showing the strongest DNA binding affinity exhibits the highest cytotoxicity. The efficiency of the complexes as fluorescent probes for detection of nuclear morphology and proteins has been evaluated by using fluorescence microscopy. Remarkably, 4, which shows strong hydrophobic forces of interaction when bound to DNA and protein, acts as fluorescent probes for detection of nuclear components in the head, and proteins in the tail, of sperms. Show less

Azocarboxamide (azcH) has been combined for the first time with [Ru-Cym] to generate metal complexes with N,N- and N,O-coordination mode, [(Cym)Ru(azc)Cl] and [(Cym)Ru(azcH)Cl](+) [PF6 ](-). Geometric and electronic structures of the complexes are reported along with their in vitro activities against different tumour cell lines and preliminary results on solution chemistry. Compound [(Cym)Ru(azc)Cl] exhibited remarkable cytotoxic properties. It was cell-type specific and had comparable IC50 values towards both cancer cells and their drug-resistant subline. A tenfold increase in the sensitivity towards [(Cym)Ru(azc)Cl] was noted for the tumour cells with depleted intracellular glutathione (GSH) level, suggesting the essential role of GSH in cell response to this compound. Show less

In recent years, Ru(iii) complexes have emerged as a new class of effective anticancer agents against tumors that proved to be resistant to all other chemotherapeutic drugs currently in clinical use. To extend our previous studies on metal complexes containing sulfur-donor ligands, we report here on the synthesis and characterization, by means of several spectroscopic and analytical techniques, some [Ru(RSDT)(3)] and [Ru(2)(RSDT)(5)]Cl complexes with dithiocarbamato ligands derived from methyl/ethyl/tert-butyl esters of sarcosine. Their electrochemical behaviour was also studied by cyclic voltammetry. All the complexes were tested for their cytotoxicity on a panel of human tumor cell lines showing highly significant antitumor activity. The chemical and biological properties of the newly synthesized complexes, were compared with those of [Ru(DMDT)(3)] and [Ru(2)(DMDT)(5)]Cl species (DMDT = N,N-dimethyldithiocarbamate) whose chemical (not biological) characterization has been already reported in literature. Show less

A water-stable phosphoramidate Ru(arene) metallodrug shows antiproliferative activity comparable to KP1019 in human cancer cell lines. This novel compound can cross-link the peptide backbone of cytochrome c, but features low apoptosis inducing properties. Show less

Eight ruthenium(ii) compounds of the general formula [(η(5)-C5H5)Ru(N-N)(PPh3)][PF6] were rationally designed, exhibiting high cytotoxicity against HCT116 human colon cancer cells, with IC50 between 14.56 and 1.56 μM; importantly, compounds 5Ru and 6Ru are the first reported ruthenium glycoconjugates exploiting glucose transporters, widely overexpressed in cancer, for cellular uptake. Show less

The reaction of [Ru(CO)₆Cl₂], 1, with N[combining low line]³-methylbenzimidazole (MBI) and 5,6-dimethylbenzimidazole (DMBI) afforded two new complexes with the general formula fac-[Ru^II(CO)₃Cl₂L], L = MBI (2) or DMBI (4). Crystals of cis,trans-[Ru^II(CO)₂Cl₂(N[combining low line]³-MBI)₂], 3, were also obtained from the mother liquor that produced 2. In the presence of water, the dissociation of Ru-N, Ru-Cl and Ru-CO bonds occurred as a function of time, water content and pH. Density functional theory structure simulations/optimizations were carried out at the Becke3LYP level of theory for evaluating the relative stability of possible conformers. ESI-MS studies revealed the ability of the complexes to link model proteins, such as lysozyme, bovine pancreatic ribonuclease and cytochrome c, with the partial release of the heteroaromatic base, chlorido and carbonyl ligands. X-ray diffraction studies on crystals grown from a solution of HEWL and 2 showed the partial removal of chloride and CO. Cytotoxicity tests yielded two-digit micromolar IC₅₀ values in CH1/PA-1 and SW480 cancer cells. In contrast to CORM-3 and 2, a significantly reduced tumor growth was observed with 4 in the murine colon cancer CT-26 model in vivo. Show less

Title: Ru(III) complexes with pyrazolopyrimidines as anticancer agents: bioactivities and the underlying mechanisms. Abstract: Three ruthenium(III) complexes with pyrazolopyrimidine [Ru(Ln)(H2O)Cl3] (1-3, n = 1-3) were prepared and characterized. These Ru(III) compounds show strong cytotoxicity against six cancer cell lines and low toxicity to normal human liver cells. Particularly, they exhibited stronger cytotoxicity to SK-OV-3 cells than cisplatin. Mechanism studies revealed that complex 1 inhibited tumor cell invasion and suppressed cell proliferation, induced apoptosis by elevating the levels of intracellular ROS (reactive oxygen species) and free calcium (Ca2+), and reduced mitochondrial membrane potential (ΔΨ). It also activated the caspase cascade, accompanied with upregulation of cytochrome c, Bax, p53, Apaf-1 and downregulation of Bcl-2. Moreover, complex 1 caused cell cycle arrest at S phase by inhibiting the expression of CDC 25, cyclin A2 and CDK 2 proteins, and induced DNA damage by interacting with DNA and inhibiting the topoisomerase I enzyme. Complex 1 exhibited efficient in vivo anticancer activity in a model of SK-OV-3 tumor xenograft. Show less

Title: Polydiacetylene/lipid-coated red-emissive silica nanorods for the sustained release and ameliorated anticancer efficacy of a Ru(arene) complex bearing piperlongumine natural product. Abstract: A suitable drug delivery strategy for metallodrugs is as significant as the strategies adopted for an efficient metallodrug design. In this study, piperlongumine, which is isolated from long pepper, is coordinated with a Ru(II)-p-cymene moiety to obtain an organoruthenated complex containing the natural product (Ru(pip)). The isolated complex shows higher cytotoxicity in MCF-7 breast cancer cells than in THP-1 leukemia and HepG2 liver cancer cells. The IC50 value of the complex in non-cancerous HEK-239 cells is also almost equal to that in MCF-7 cells. Next, with an aim to modulate the antiproliferative activity of Ru(pip) using a drug delivery strategy, the complex is loaded into mesoporous silica nanorods (MSNRs), which have a higher surface area than spherical silica nanoparticles. Furthermore, the outer surface of the loaded nanorods is covered with a polydiacetylene-lipid (PL) hybrid bilayer. Given the unique optical properties of polydiacetylene, the PL coating modifies non-fluorescent MSNRs into red-emissive particles (PL-Ru(pip)@MSNRs), which can be useful for diagnostic applications. The release profile studies reveal that the ene-yne conjugation in the PL coating ensures the sustained release of the complex from nanoparticles in both physiological and simulated cancer cell media. While Ru(pip) exhibits both necrotic and apoptotic modes of cell death, PL-Ru(pip)@MSNRs preferably induce the apoptotic mode of cell death in MCF-7 and THP-1 cells. Also, the nanoformulation exhibits a higher percentage of cell cycle arrest in the G0/G1 phase than Ru(pip), as measured by flow cytometry analysis. In contrast, the in vitro antioxidant potency of the complex is decreased after being loaded into PL-coated silica nanoparticles. Show less