📚 BiometalDB

A number of reduced amino Schiff base ligands and corresponding ruthenium(III) complexes were designed and prepared based on the fact that amino acids not only possess multiple coordinate atoms but also improve the solubility of drugs in the body. The interaction of the complexes with calf thymus DNA was analyzed with spectroscopic methods of ultraviolet-visible absorption spectra, DNA competitive binding with ethidium bromide, circular dichroism spectra, and DNA melting experiments, and DNA viscosity measurements, indicating that the complexes bind to DNA primarily in the grooving mode. With respect to the ligands, the cytotoxicity in vitro of the complexes against Hela, A549, and MCF-7 cells was much enhanced, with most of the IC₅₀ values less than 50 μM or even comparable with those of cisplatin. 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

Ruthenium complexes have been investigated for various biological applications by virtue of their radical scavenging, DNA binding, receptor binding, and cytotoxic abilities; especially the possible potential application of these complexes in photodynamic therapy (PDT). This study focuses on the synthesis, structural characterization and biological application (pertaining to its cytotoxicity and radical generation) of ruthenium complexed with salicylaldehyde fumaryl-dihydrazone (slfhH₄ ), salicylaldehyde glutaryl-di-hydrazone (slfgH₄ ) and 2,2'-bipyridine (bpy). During the synthesis, the anticipated complex was precipitated out but as serendipity, Ruthenium(II) tris (2,2'-bipyridyl) monochloride nonahydrate {[Ru(bpy)₃ ]²⁺ .Cl.9H₂ O} (RBMN) and Ruthenium(II) tris (2,2'-bipyridyl) monochloride septahydrate {[Ru(bpy)₃ ]²⁺ .Cl.7H₂ O}(RBMS) were crystallized from the filtrate. The crystal structure of complexes RBMN and RBMS were determined by a single-crystal X-ray diffraction methods and it showed that chlorine anion lies at the crystallographic axis and forms a halogen hydrogen-bonded organic framework (XHOF) to provide the stability. In comparison with similar structures in Cambridge Crystallographic Data Center (CCDC) revealed that the nature of the XHOF framework and the layered packing are conserved. The compounds showed excellent cytotoxic ability (against L6 cells) and the nitro blue tetrazolium (NBT) assay upon irradiation to light revealed its ability to produce reactive oxygen species (ROS). The presence of partially occupied water molecules in the layered organization within the crystal packing mimics the release of ROS resulting in cytotoxicity. The structural results together with the biological data make these complexes interesting candidates for potential photosensitizers for PDT applications. Show less

Photodynamic therapy (PDT) is an anticancer/antibacterial strategy in which photosensitizers (PSs), light, and molecular oxygen generate reactive oxygen species and induce cell death. PDT presents greater selectivity towards tumor cells than conventional chemotherapy; however, PSs have limitations that have prompted the search for new molecules featuring more favorable chemical-physical characteristics. Curcumin and its derivatives have been used in PDT. However, low water solubility, rapid metabolism, interference with other drugs, and low stability limit curcumin use. Chemical modifications have been proposed to improve curcumin activity, and metal-based PSs, especially ruthenium(II) complexes, have attracted considerable attention. This study aimed to characterize six Ru(II)-arene curcuminoids for anticancer and/or antibacterial PDT. The hydrophilicity, photodegradation rates, and singlet oxygen generation of the compounds were evaluated. The photodynamic effects on human colorectal cancer cell lines were also assessed, along with the ability of the compounds to induce ROS production, apoptotic, necrotic, and/or autophagic cell death. Overall, our encouraging results indicate that the Ru(II)-arene curcuminoid derivatives are worthy of further investigation and could represent an interesting option for cancer PDT. Additionally, the lack of significant in vivo toxicity on the larvae of Galleria mellonella is an important finding. Finally, the photoantimicrobial activity of HCurc I against Gram-positive bacteria is indeed promising. Show less

Novel full-sandwich (η⁵-Cp)-Ru-paraphenylene complexes with the general formula [(η⁵-Cp)_nRu(η⁶-L)](PF₆)_n where n = 1-3 and L = biphenyl, p-terphenyl and p-quaterphenyl, were synthesized and characterized by means of spectroscopic and analytical techniques. The structures of the complexes [(η⁵-Cp)Ru(η⁶-biphenyl)](PF₆) (1), [(η⁵-Cp)Ru(η⁶-terphenyl)](PF₆) (3) and [(η⁵-Cp)₂Ru(η⁶-terphenyl)](PF₆)₂ (4) was determined by X-ray single crystal methods. The interaction of the complexes [(η⁵-Cp)Ru(η⁶-quaterphenyl)]Cl, (6)Cl, and [(η⁵-Cp)₂Ru(η⁶-quaterphenyl)]Cl₂, (7)Cl₂, with the DNA duplex d(5'-CGCGAATTCGCG-3')₂ was studied using NMR techniques. The results showed that both complexes interacted non-specifically with both the minor and major grooves of the helix. Specifically, (6)Cl exhibited partial binding through intercalation between the T7 and T8 bases of the sequence without disrupting the C-G and A-T hydrogen bonds. Fluorometric determination of the complexes' binding constants revealed a significant influence of the number of connected phenyl rings in the paraphenylene ligand (L) on the binding affinity of their complexes with the d(5'-CGCGAATTCGCG-3')₂. The complexes (6)Cl and (7)Cl₂ were found to be highly cytotoxic against the A549 lung cancer cell line, with complex (6) being more effective than (7) (IC₅₀ for (6)Cl: 17.45 ± 2.1 μΜ, IC₅₀ for (7)Cl₂: 65.83 ± 1.8 μΜ) and with a selectivity index (SI) (SI for (6)Cl: 1.1 and SI for (7)Cl₂: 4.8). Show less

With the aim of enhancing the biological activity of ruthenium-nitrosyl complexes, new compounds with four equatorially bound indazole ligands, namely, trans-[RuCl(Hind)₄(NO)]Cl₂·H₂O ([3]Cl₂·H₂O) and trans-[RuOH(Hind)₄(NO)]Cl₂·H₂O ([4]Cl₂·H₂O), have been prepared from trans-[Ru(NO₂)₂(Hind)₄] ([2]). When the pH-dependent solution behavior of [3]Cl₂·H₂O and [4]Cl₂·H₂O was studied, two new complexes with two deprotonated indazole ligands were isolated, namely [RuCl(ind)₂(Hind)₂(NO)] ([5]) and [RuOH(ind)₂(Hind)₂(NO)] ([6]). All prepared compounds were comprehensively characterized by spectroscopic (IR, UV-vis, ¹H NMR) techniques. Compound [2], as well as [3]Cl₂·2(CH₃)₂CO, [4]Cl₂·2(CH₃)₂CO, and [5]·0.8CH₂Cl₂, the latter three obtained by recrystallization of the first isolated compounds (hydrates or anhydrous species) from acetone and dichloromethane, respectively, were studied by X-ray diffraction methods. The photoinduced release of NO in [3]Cl₂ and [4]Cl₂ was investigated by cyclic voltammetry and resulting paramagnetic NO species were detected by EPR spectroscopy. The quantum yields of NO release were calculated and found to be low (3-6%), which could be explained by NO dissociation and recombination dynamics, assessed by femtosecond pump-probe spectroscopy. The geometry and electronic parameters of Ru species formed upon NO release were identified by DFT calculations. The complexes [3]Cl₂ and [4]Cl₂ showed considerable antiproliferative activity in human cancer cell lines with IC₅₀ values in low micromolar or submicromolar concentration range and are suitable for further development as potential anticancer drugs. p53-dependence of Ru-NO complexes [3]Cl₂ and [4]Cl₂ was studied and p53-independent mode of action was confirmed. The effects of NO release on the cytotoxicity of the complexes with or without light irradiation were investigated using NO scavenger carboxy-PTIO. Show less

New ruthenium methyl-cyclopentadienyl compounds bearing bipyridine derivatives with the general formula [Ru(η⁵-MeCp)(PPh₃)(4,4'-R-2,2'-bpy)]⁺ (Ru1, R = H; Ru2, R = CH₃; and Ru3, R = CH₂OH) have been synthesized and characterized by spectroscopic and analytical techniques. Ru1 crystallized in the monoclinic P2₁/ c, Ru2 in the triclinic P1̅, and Ru3 in the monoclinic P2₁/ n space group. In all molecular structures, the ruthenium center adopts a "piano stool" distribution. Density functional theory calculations were performed for all complexes, and the results support spectroscopic data. Ru1 and Ru3 were poor substrates of the main multidrug resistance human pumps, ABCB1, ABCG2, ABCC1, and ABCC2, while Ru2 displayed inhibitory properties of ABCC1 and ABCC2 pumps. Importantly, all compounds displayed a very high cytotoxic profile for ovarian cancer cells (sensitive and resistant) that was much more pronounced than that observed with cisplatin, making them very promising anticancer agents. Show less

Half-sandwich metal-based anticancer complexes suffer from uncertain targets and mechanisms of action. Herein we report the observation of the images of half-sandwich iridium and ruthenium complexes in cells detected by confocal microscopy. The confocal microscopy images showed that the cyclopentadienyl iridium complex 1 mainly accumulated in nuclei in A549 lung cancer cells, whereas the arene ruthenium complex 3 is located in mitochondria and lysosomes, mostly in mitochondria, although both complexes entered A549 cells mainly through energy-dependent active transport. The nuclear morphological changes caused by Ir complex 1 were also detected by confocal microscopy. Ir complex 1 is more potent than cisplatin toward A549 and HeLa cells. DNA binding studies involved interaction with the nucleobases 9-ethylguanine, 9-methyladenine, ctDNA, and plasmid DNA. The determination of bovine serum albumin binding was also performed. Hydrolysis, stability, nucleobase binding, and catalytic NAD⁺/NADH hydride transfer tests for complexes 1 and 3 were also carried out. Both complexes activated depolarization of mitochondrial membrane potential and intracellular ROS overproduction and induced cell apoptosis. Complex 3 arrested the cell cycle at the G₀/G₁ phase by inactivation of CDK 4/cyclin D1. This work paves the way to track and monitor half-sandwich metal complexes in cells, shines a light on understanding their mechanism of action, and indicates their potential application as theranostic agents. Show less

Ruthenium(II) arene complexes of 1,4,7-triaza-9-phosphatricyclo[5.3.2.1]tridecane (CAP) were obtained. Cytotoxicity studies against cancer cell lines reveal higher activity than the corresponding PTA analogues and, in comparison to the effects on noncancerous cells, the complexes are endowed with a reasonable degree of cancer cell selectivity. Show less

In this study, six half-sandwich luminescent iridium (Ir) and ruthenium (Ru) anticancer complexes bearing P^P-chelating ligands 1,2-bis(diphenylphosphino)benzene (dppbz) and 1,8-bis(diphenylphosphino)naphthalene (dppn) were synthesized and characterized via1H-NMR spectroscopy, 31P-NMR spectroscopy, mass spectrometry, elemental analysis and X-ray crystallography. All the complexes displayed more potent anticancer activity than cisplatin towards A549 lung cancer cells and HeLa cervical cancer cells, especially the most potent iridium complex Ir3, which was 73 times more potent than cisplatin against A549 cells. Different from cisplatin, no nucleobase adducts of Ir3 were detected. With the help of the self-luminescence of complex Ir3 and confocal microscopy, it was observed that Ir3 efficiently penetrated into the A549 cells via energy-dependent active transport, and specifically accumulated in lysosomes, affected the permeabilization of the lysosomal membranes and induced caspase-dependent cell death through lysosomal damage. Both apoptosis and autophagy of the A549 cells were observed. The reactive oxygen species (ROS) elevation, reduction of the mitochondrial membrane potential and cell cycle arrest at the G0/G1 phase also contributed to the observed cytotoxicity of Ir3. We demonstrate that these half-sandwich Ir and Ru anticancer complexes have different anticancer mechanism of action from that of cisplatin, which can be developed as potential multifunctional theranostic platforms that combine bioimaging and anticancer capabilities. Show less

A series of neutral ruthenium(II) arene complexes [(arene)Ru(Q^R)Cl] (arene = p-cymene (cym) or hexamethylbenzene (hmb)) containing 4-acyl-5-pyrazolonate Q^R ligands with different electronic and steric substituents (R = 4-cyclohexyl, 4-stearoyl, or 4-adamantyl) and related ionic complexes [(arene)Ru(Q^R)(PTA)][PF₆] (PTA = 1,3,5-triaza-7-phosphaadamantane) were synthesized and characterized by spectroscopy (IR, UV-vis, ESI-MS, and ¹H and ¹³C NMR), elemental analysis, X-ray crystallography, and density functional theory studies. The cytotoxicity of the proligands and metal complexes was evaluated in vitro against human ovarian carcinoma cells (A2780 and A2780cisR), as well as against nontumorous human embryonic kidney (HEK293) cells. In general the cationic PTA-containing complexes are more cytotoxic than their neutral precursors with a chloride ligand in place of the PTA. Moreover, the complexes do not show cross-resistance and are essentially equally cytotoxic to both the A2780 and A2780cisR cell lines, although they only show limited selectivity toward the cancer cell lines. Show less

Five heteroleptic tris-diimine ruthenium(II) complexes [RuL(N^N)₂](PF₆)₂ (where L is 3,8-di(benzothiazolylfluorenyl)-1,10-phenanthroline and N^N is 2,2'-bipyridine (bpy) (1), 1,10-phenanthroline (phen) (2), 1,4,8,9-tetraazatriphenylene (tatp) (3), dipyrido[3,2-a:2',3'-c]phenazine (dppz) (4), or benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn) (5), respectively) were synthesized. The influence of π-conjugation of the ancillary ligands (N^N) on the photophysical properties of the complexes was investigated by spectroscopic methods and simulated by density functional theory (DFT) and time-dependent DFT. Their ground-state absorption spectra were characterized by intense absorption bands below 350 nm (ligand L localized ¹π,π* transitions) and a featureless band centered at ∼410 nm (intraligand charge transfer (¹ILCT)/¹π,π* transitions with minor contribution from metal-to-ligand charge transfer (¹MLCT) transition). For complexes 4 and 5 with dppz and dppn ligands, respectively, broad but very weak absorption (ε < 800 M^-1 cm^-1) was present from 600 to 850 nm, likely emanating from the spin-forbidden transitions to the triplet excited states. All five complexes showed red-orange phosphorescence at room temperature in CH₂Cl₂ solution with decreased lifetimes and emission quantum yields, as the π-conjugation of the ancillary ligands increased. Transient absorption (TA) profiles were probed in acetonitrile solutions at room temperature for all of the complexes. Except for complex 5 (which showed dppn-localized ³π,π* absorption with a long lifetime of 41.2 μs), complexes 1-4 displayed similar TA spectral features but with much shorter triplet lifetimes (1-2 μs). Reverse saturable absorption (RSA) was demonstrated for the complexes at 532 nm using 4.1 ns laser pulses, and the strength of RSA decreased in the order: 2 ≥ 1 ≈ 5 > 3 > 4. Complex 5 is particularly attractive as a broadband reverse saturable absorber due to its wide optical window (430-850 nm) and long-lived triplet lifetime in addition to its strong RSA at 532 nm. Complexes 1-5 were also probed as photosensitizing agents for in vitro photodynamic therapy (PDT). Most of them showed a PDT effect, and 5 emerged as the most potent complex with red light (EC₅₀ = 10 μM) and was highly photoselective for melanoma cells (selectivity factor, SF = 13). Complexes 1-5 were readily taken up by cells and tracked by their intracellular luminescence before and after a light treatment. Diagnostic intracellular luminescence increased with increased π-conjugation of the ancillary N^N ligands despite diminishing cell-free phosphorescence in that order. All of the complexes penetrated the nucleus and caused DNA condensation in cell-free conditions in a concentration-dependent manner, which was not influenced by the identity of N^N ligands. Although the mechanism for photobiological activity was not established, complexes 1-5 were shown to exhibit potential as theranostic agents. Together the RSA and PDT studies indicate that developing new agents with long intrinsic triplet lifetimes, high yields for triplet formation, and broad ground-state absorption to near-infrared (NIR) in tandem is a viable approach to identifying promising agents for these applications. Show less

α-Diimines are among the most robust and versatile ligands available in synthetic coordination chemistry, possessing finely tunable steric and electronic properties. A series of novel cationic ruthenium(II) p-cymene complexes bearing simple α-diimine ligands, [(η⁶- p-cymene)RuCl{κ² N-(HCNR)₂}]NO₃ (R = Cy, [1]NO₃; R = 4-C₆H₁₀OH, [2]NO₃; R = 4-C₆H₄OH, [3]NO₃), were prepared in near-quantitative yields as their nitrate salts. [2]NO₃ displays high water solubility. The potential of the α-diimine ligand in [3]NO₃ as a carrier of bioactive molecules was investigated via esterification reactions with the hydroxyl groups. Thus, the double-functionalized derivatives [(η⁶- p-cymene)RuCl{κ² N-(HCN(4-C₆H₄OCO-R))₂}]NO₃ (R = aspirinate, [5]NO₃; valproate, [6]NO₃) and also [4]Cl (R = Me) were obtained in good-to-high yields. UV-vis and multinuclear NMR spectroscopy and cyclic voltammetric studies in aqueous solution revealed only minor ruthenium chloride hydrolytic cleavage, biologically accessible reduction potentials, and pH-dependent behavior of [3]NO₃. Density functional theory analysis was performed in order to compare the Ru-Cl bond strength in [1]⁺ with the analogous ethylenediamine complex, showing that the higher stability observed in the former is related to the electron-withdrawing properties of the α-diimine ligand. In vitro cytotoxicity studies were performed against tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK-293) cell lines, with the complexes bearing simple α-diimine ligands ranging from inactive to IC₅₀ values in the low micromolar range. The complexes functionalized with bioactive components, i.e., [5]NO₃ and [6]NO₃, exhibited a marked increase in the cytotoxicity with respect to the precursor [3]NO₃. Show less

Three pyrazolone-based hydrazone ligands HL' (HL' in general; in detail, HL1 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl)(phenyl)methylene)-1-(2,4-nitrophenyl)hydrazine, HL2 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl) (phenyl)methylene)-1-(4-nitrophenyl)hydrazine, and HL3 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl)(phenyl)methylene)-1-(pyridin-2-yl)hydrazine) have been prepared starting from 4-benzoyl-3-methyl-1-phenyl-1 H-pyrazol-5(4 H)-one and fully characterized in the solid state and solution, where the existing tautomeric forms were identified by taking advantage of natural abundance ¹H-¹⁵N coupling in {¹H-¹⁵N}-HSQC and {¹H-¹⁵N}-HMBC NMR spectroscopy. Then, six half-sandwich arene-ruthenium(II) derivatives (arene = hexamethylbenzene and p-cymene) of composition [(arene)Ru(L')Cl] have been synthesized and fully characterized by IR, ¹H, and ¹³C NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis, and density functional theory calculations. The crystal structures of three complexes, together with the E configurational isomer (with respect to the C═N double bond) of the free proligand HL2 and the zwitterionic proligand HL3 were determined by X-ray analysis. The anionic ligands L1 and L2 were found bonded to ruthenium in the N,O-form, while L3 coordinates the metal in the N,N-form affording five-membered chelating rings. The cytotoxicity of the complexes was evaluated against human breast adenocarcinoma cells (MCF-7 and MCF-7CR), as well as against nontumorigenic human breast (MCF-10A) cells and compared to the free ligand and cisplatin. Show less

The ruthenium(II) complexes [RuCl(L¹)(L³)]Cl (1), [RuCl(L¹)(L⁴)]Cl (2), [RuCl(L²)(L⁴)]Cl (3), [RuCl(L¹)(L⁵)]Cl (4), and [RuCl(L²)(L⁵)]Cl (5) of NNN-donor dipicolylamine (dpa) bases (L⁴, L⁵) having BODIPY (boron-dipyrromethene) moieties, NN-donor phenanthroline derivatives (L¹, L²), and benzyldipicolylamine (bzdpa, L³) were prepared and characterized by spectroscopic techniques and their cellular localization/uptake and photocytotoxicity studied. Complex 1, as its PF₆ salt (1a), has been structurally characterized with help of a single-crystal X-ray diffraction technique. It has a RuN₅Cl core with the Cl bonded trans to the amine nitrogen atom of bzdpa. The complexes showed intense absorption spectral bands near 500 nm (ε ≈ 58000 M^-1 cm^-1) in 2 and 3 and 654 nm (ε ≈ 80000 M^-1 cm^-1) in 4 and 5 in 1/1 DMSO/DPBS (v/v). Complex 5 having biotin and PEGylated-disteryl BODIPY gave a singlet oxygen quantum yield (Φ_Δ) of ∼0.65 in DMSO. Complex 5 exhibited remarkable PDT (photodynamic therapy) activity (IC₅₀ ≈ 0.02 μM) with a photocytotoxicity index (PI) value of >5000 in red light of 600-720 nm in A549 cancer cells. The biotin-conjugated complexes showed better photocytotoxicity in comparison to nonbiotinylated analogues in A549 cells. The complexes displayed less toxicity in HPL1D normal cells in comparison to A549 cancer cells. The emissive BODIPY complexes 3 and 5 (Φ_F ≈ 0.07 in DMSO) showed significant mitochondrial localization. Show less

Some of the largest improvements in clinical outcomes for patients with solid cancers observed over the past 3 decades have been from concurrent treatment with chemotherapy and radiotherapy (RT). The lethal effects of RT on cancer cells arise primarily from damage to DNA. Ruthenium (Ru) is a transition metal of the platinum group, with potentially less toxicity than platinum drugs. We postulated that ruthenium-arene complexes are radiosensitisers when used in combination with RT. We screened 14 ruthenium-arene complexes and identified AH54 and AH63 as supra-additive radiosensitisers by clonogenic survival assays and isobologram analyses. Both complexes displayed facial chirality. At clinically relevant doses of RT, radiosensitisation of cancer cells by AH54 and AH63 was p53-dependent. Radiation enhancement ratios for 5-10 micromolar drug concentrations ranged from 1.19 to 1.82. In p53-wildtype cells, both drugs induced significant G2 cell cycle arrest and apoptosis. Colorectal cancer cells deficient in DNA damage repair proteins, EME1 and MUS81, were significantly more sensitive to both agents. Both drugs were active in cancer cell lines displaying acquired resistance to oxaliplatin or cisplatin. Our findings broaden the potential scope for these drugs for use in cancer therapy, including combination with radiotherapy to treat colorectal cancer. Show less