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The stable complex [bis(toluene-3,4-dithiolato)copper(III)][NEt3H] has been synthesised and characterised as a square-planar Cu(III) complex by X-ray photoelectron spectroscopy, cyclic voltammetry and DFT calculations. Intriguingly, when fragmented in FTICR-MS, an unusual [(toluene-3,4-dithiolate)Cu(III)(peroxide)]− complex is formed by reaction with oxygen. Natural 1,2-dithiolenes known to bind molybdenum might stabilise Cu(III) in vivo. Show less

Abstract A series of palladium(II) complexes with 1H- and 2H-tetrazole ligands (2-isopropyl-5-R-2H-tetrazoles and 1H-tetrazol-1-ylcarboxylic acids) was synthesized. Structure of the obtained compounds was confirmed by 1H and 13C NMR spectroscopy, high-resolution mass spectrometry, and single crystal X-ray diffraction analysis. According to the spectrophotometry data, the complexes are weakly bound to DNA. The cytotoxic activity of the obtained palladium complexes was studied in vitro. Show less

Gold(I) complexes with phosphine ligands—[Au(TrippyPhos)Cl] (1) (TrippyPhos = 1-[2-[bis(tert-butyl)phosphino]phenyl]-3,5-diphenyl-1H-pyrazole), [Au(BippyPhos)Cl]0.5CH2Cl2 (2) (BippyPhos = 5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole), and [Au(meCgPPh)Cl] (3) (meCgPPh = 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane—were investigated as types of bioactive gold metallodrugs. Complexes (1)–(3) were characterized using IR, 1H, 13C, 31P NMR spectroscopy, elemental analysis and mass spectrometry (FAB-MS). Complexes of (1) and (2) exhibited substantial in vitro cytotoxicity (IC50 = 0.5–7.0 μM) against both the cisplatin-sensitive and -resistant variants of the A2780 human ovarian carcinoma cell line, as well as against the A549 human lung carcinoma, K562 chronic myelogenous leukemia, and HeLa (human cervix carcinoma) cells. However, among the compounds studied, complex (2) showed the most promising biological properties: the highest stability in biologically relevant media, selectivity towards cancer cells over the non-cancer cells (HUVEC, human umbilical vein endothelial cells), and the highest inhibitory effect on cytosolic NADPH-dependent reductases in A2780 and A2780cis cells among the gold complexes under analysis. Show less

Ruthenium(II) complexes (Ru1-Ru5), with the general formula [Ru(N-S)(dppe)₂]PF₆, bearing two 1,2-bis(diphenylphosphino)ethane (dppe) ligands and a series of mercapto ligands (N-S), have been developed. The combination of these ligands in the complexes endowed hydrophobic species with high cytotoxic activity against five cancer cell lines. For the A549 (lung) and MDA-MB-231 (breast) cancer cell lines, the IC₅₀ values of the complexes were 288- to 14-fold lower when compared to cisplatin. Furthermore, the complexes were selective for the A549 and MDA-MB-231 cancer cell lines compared to the MRC-5 nontumor cell line. The multitarget character of the complexes was investigated by using calf thymus DNA (CT DNA), human serum albumin, and human topoisomerase IB (hTopIB). The complexes potently inhibited hTopIB. In particular, complex [Ru(dmp)(dppe)₂]PF₆ (Ru3), bearing the 4,6-diamino-2-mercaptopyrimidine (dmp) ligand, effectively inhibited hTopIB by acting on both the cleavage and religation steps of the catalytic cycle of this enzyme. Molecular docking showed that the Ru1-Ru5 complexes have binding affinity by active sites on the hTopI and hTopI-DNA, mainly via π-alkyl and alkyl hydrophobic interactions, as well as through hydrogen bonds. Complex Ru3 displayed significant antitumor activity against murine melanoma in mouse xenograph models, but this complex did not damage DNA, as revealed by Ames and micronucleus tests. Show less

Two new arene ruthenium(II) complexes with chemical formula [Ru2(η6‐p‐cymene)2(μ‐L1)(μ‐Cl)Cl2][Ru]‐1and [Ru(η6‐p‐cymene)(L2)Cl2][Ru]‐2(L1 =5‐phenyl‐2H‐tetrazole andL2= 2‐(2H‐tetrazol‐5‐yl)pyridine) were synthesized by the reaction of [{(η6‐p‐cymene)RuCl2}2] with two bidentate ligands L1 and L2. Both the complexes were structurally characterized using single‐crystal X‐ray diffraction and other analytical techniques. The X‐ray crystal structures of both the complexes revealed the coordination of tetrazolate ligands to two Ru(II) centres in bridging mode in[Ru]‐1, whereas one Ru(II) centre in[Ru]‐2in chelating fashion, with overall pseudo‐octahedral geometry. The resulted complexes were screened for their cytotoxic activity against three different cancer cell lines, HCT116 (colon cancer), HepG2 (liver cancer) and MCF7 (breast cancer) under in vitro conditions. Interestingly,[Ru]‐1showed much higher cytotoxicity with respect to[Ru]‐2against all the screened cancer cell lines and even better than cisplatin. For exploring the mechanism of action of[Ru]‐1, reactive oxygen species (ROS) production, alterations in mitochondrial membrane potential and gene expression profiling of apoptosis related genes (Bcl2, caspase‐3 and caspase‐9) were also evaluated. The cancerous cells treated with[Ru]‐1showed an increase in intracellular ROS levels, disruption of mitochondrial membrane potential, up‐regulation of proapoptotic caspase‐3 and caspase‐9 and down‐regulation of antiapoptotic Bcl2. The results concluded that[Ru]‐1induced apoptosis through oxidative stress mediated activation of intrinsic pathway by generating intracellular ROS, loss of MMP and alteration of expression of apoptosis related genes. In addition, antimetastatic activity of[Ru]‐1was observed by wound healing assay showing anti‐migratory property. The dual properties, antimetastatic activity and high cytotoxicity make[Ru]‐1potent platform for the development of new anticancer agents. Show less

Platinum-based complexes are one of the most successful chemotherapeutic agents having a significant ground in cancer chemotherapy despite their side effects. During the past few decades, Ru(II) complexes have been emerging as efficient alternatives owing to their promising activities against platinum-resistant cancer. The pathway of action, lipophilicity, and cytotoxicity of a Pt or Ru complex may be tuned by varying the attached ligands, the coordination mode, and the leaving group. In this work, we report a family of Pt(II) and Ru(II) complexes (1-5) of three N,O and N,N donor-based trimethoxyanilines containing Schiff bases with the general formula [Pt^II(L)(DMSO)Cl], [Ru^II(L)(p-cymene)Cl], [Ru^II(L)(p-cymene)Cl]⁺, and [Pt^II(L)Cl₂]. All of the complexes are characterized by different analytical techniques. ¹H NMR and electrospray ionization mass spectrometry (ESI-MS) data suggest that the N,O-coordinated Pt(II) complexes undergo slower aquation compared to the Ru(II) analogues. The change of the coordination mode to N,N causes the Ru complexes to be more inert to aquation. The N,O-coordinating complexes show superiority over N,N-coordinating complexes by displaying excellent in vitro antiproliferative activity against different aggressive cancer cells, viz., triple-negative human metastatic breast adenocarcinoma MDA-MB-231, human pancreatic carcinoma MIA PaCa-2, and hepatocellular carcinoma Hep G2. In vitro cytotoxicity studies suggest that Pt(II) complexes are more effective than their corresponding Ru(II) analogues, and the most cytotoxic complex 3 is 10-15 times more toxic than the clinical drugs cisplatin and oxaliplatin against MDA-MB-231 cells. Cellular studies show that all of the N,O-coordinated complexes (1-3) initiate disruption of the microtubule network in MDA-MB-231 cells in a dose-dependent manner within 6 h of incubation and finally lead to the arrest of the cell cycle in the G2/M phase and render apoptotic cell death. The disruption of the microtubule network affects the agility of the cytoskeleton rendering inhibition of tyrosine phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), a key step in angiogenesis. Complexes 1 and 2 inhibit VEGFR2 phosphorylation in a dose-dependent fashion. Among the Pt(II) and Ru(II) complexes, the former displays higher cytotoxicity, a stronger effect on the cytoskeleton, better VEGFR2 inhibition, and strong interaction with the model nucleobase 9-ethylguanine (9-EtG). Show less

The antiproliferative activity of three cyclometalated Ru(II) complexes with the formula [Ru(bpy)₂L]PF₆, where bpy = 2,2'-bipyridine, Ru1: L1 = phenanthro[4,5-fgh]quinoxaline; Ru2: L2 = benzo[f]naphtho[2,1-h]quinoxaline; and Ru3: L3 = phenanthro[9,10-b]pyrazine, have been synthesized and characterized. The lipophilicity of the three Ru(II) complexes was modulated by the alteration of the planarity in the ligands of the complexes. With appropriate lipophilicity, Ru1-Ru3 exhibited mitochondrial accumulating property and cytotoxic activity against a spectrum of cancer cell lines. The underlying mechanism study indicated that these Ru(II) complexes can selectively accumulate in mitochondria and disrupt physiological processes, including the redox balance and energy generation in cancer cells. Elevation of iron content in triple-negative breast cancer (MDA-MB-231 cells) was observed after treatment with Ru(II) complexes, which may contribute to the production of reactive oxygen species (ROS) via Fenton reaction chemistry. Besides, the Ru(II) complexes decreased the intracellular glutathione (GSH) in cancer cells, leading to the failure in the cells to combat oxidative damage. Both of the mentioned processes contribute to the high oxidative stress and eventually lead to cancer cell death. On the other hand, Ru1-Ru3 significantly induced the depletion of adenosine triphosphate (ATP), causing disturbance of energy generation. Moreover, the results of wound-healing assay and transwell invasion assay, as well as the tube formation assay indicated the anti-migration and anti-angiogenesis properties of Ru1-Ru3. Our study demonstrated that these Ru(II) complexes are promising chemotherapeutic agents with oxidative stress induction and energy generation disturbance. Show less

The assumption that there was a “water problem” at the emergence of life—that the Hadean Ocean was simply too wet and salty for life to have emerged in it—is here subjected to geological and experimental reality checks. The “warm little pond” that would take the place of the submarine alkaline vent theory (AVT), as recently extolled in the journal Nature, flies in the face of decades of geological, microbiological and evolutionary research and reasoning. To the present author, the evidence refuting the warm little pond scheme is overwhelming given the facts that (i) the early Earth was a water world, (ii) its all-enveloping ocean was never less than 4 km deep, (iii) there were no figurative “Icelands” or “Hawaiis”, nor even an “Ontong Java” then because (iv) the solidifying magma ocean beneath was still too mushy to support such salient loadings on the oceanic crust. In place of the supposed warm little pond, we offer a well-protected mineral mound precipitated at a submarine alkaline vent as life’s womb: in place of lipid membranes, we suggest peptides; we replace poisonous cyanide with ammonium and hydrazine; instead of deleterious radiation we have the appropriate life-giving redox and pH disequilibria; and in place of messy chemistry we offer the potential for life’s emergence from the simplest of geochemically available molecules and ions focused at a submarine alkaline vent in the Hadean—specifically within the nano-confined flexible and redox active interlayer walls of the mixed-valent double layer oxyhydroxide mineral, fougerite/green rust comprising much of that mound. Problem”(sic), the Illusory Pond and Life’s Submarine Emergence—A Review. Life 2021, 11, 429. https:// doi.org/10.3390/life11050429 Show less

Organometallic Ru-arene complexes are promising as anticancer agents, but the lack of tumor uptake and poor solubility in the physiological medium impede their development. In order to deal with these challenges, we developed gold nanoparticles coated with Ru(arene)-functionalized PNVP-Py, where PNVP-Py is pyridine end-functionalized poly(N-vinylpyrrolidone). It is demonstrated that these particles exhibit higher anti-proliferative activity than the individual organometallic ruthenium(ii) complex of the type [Ru(η6-p-cymene)(NN)Cl]PF6, where NN is bis(4-methoxyphenylimino)acenaphthene, against colorectal adenocarcinoma cell lines. More specifically, a RuII(η6-p-cymene) complex containing a NN bidentate ligand has been prepared and characterized by spectral studies and X-ray crystallography. To tether the isolated complex onto the surface of the AuNPs, PNVP-Py, which contains a pyridine group at one end to coordinate to the Ru-complex and a suitable functional group at the other end to bind on the surface of the AuNPs, has been prepared and utilized to obtain the macromolecular complex [Ru(η6-p-cymene)(NN)(PNVP-Py)]Cl2. Next, stable Ru(p-cym)(NN)(PNVP-Py)@AuNPs were obtained via a ligand exchange reaction of citrate-stabilized AuNPs with a macromolecular complex by a direct 'grafting to' approach and characterized well. Despite the lower DNA cleavage activity, the nanoconjugate exhibits better cytotoxicity than the individual complex against HT-29 colorectal adenocarcinoma cells on account of its enhanced permeability across the cell membrane. The AO/EB staining assay revealed that the nanoconjugate is able to induce an apoptotic mode of cell death, which was further quantitatively evaluated by Annexin V-FITC/PI double assay. An immunofluorescence assay indicated the higher potency of the nanoconjugate to inhibit cyclin D1 gene expression that is required for cancer cell growth. To the best of our knowledge, this is the first report of the modification of an organometallic Ru(arene) complex into a Ru(arene)metallopolymer-gold nanoconjugate for the development of ruthenium-based nanomedicine for cancer treatment. Show less

The ability to detect oxygen availability is a ubiquitous attribute of aerobic organisms. However, the mechanism(s) that transduce oxygen concentration or availability into appropriate physiological responses is less clear and often controversial. This review will make the case for oxygen-dependent metabolism of hydrogen sulfide (H2S) and polysulfides, collectively referred to as reactive sulfur species (RSS) as a physiologically relevant O2 sensing mechanism. This hypothesis is based on observations that H2S and RSS metabolism is inversely correlated with O2 tension, exogenous H2S elicits physiological responses identical to those produced by hypoxia, factors that affect H2S production or catabolism also affect tissue responses to hypoxia, and that RSS efficiently regulate downstream effectors of the hypoxic response in a manner consistent with a decrease in O2. H2S-mediated O2 sensing is then compared to the more generally accepted reactive oxygen species (ROS) mediated O2 sensing mechanism and a number of reasons are offered to resolve some of the confusion between the two. Show less

Au2phen ((2,9-dimethyl-1,10-phenanthroline)2Au2(µ-O)2)(PF6)2 and Auoxo6 ((6,6′-dimethyl-2,2′-bipyridine)2Au2(µ-O)2)(PF6)2 are two structurally related gold(III) complexes that were previously reported to display relevant and promising anticancer properties in vitro toward a large number of human cancer cell lines. To expand the knowledge on the molecular mechanisms through which these gold(III) complexes trigger apoptosis in cancer cells, further studies have been performed using A2780 ovarian cancer cells as reference models. For comparative purposes, parallel studies were carried out on the gold(III) complex AuL12 (dibromo(ethylsarcosinedithiocarbamate)gold(III)), whose proapoptotic profile had been earlier characterized in several cancer cell lines. Our results pointed out that all these gold(III) compounds manifest a significant degree of similarity in their cellular and proapoptotic effects; the main observed perturbations consist of potent thioredoxin reductase inhibition, disruption of the cell redox balance, impairment of the mitochondrial membrane potential, and induction of associated metabolic changes. In addition, evidence was gained of the remarkable contribution of ASK1 (apoptosis-signal-regulating kinase-1) and AKT pathways to gold(III)-induced apoptotic signaling. Overall, the observed effects may be traced back to gold(III) reduction and subsequent formation and release of gold(I) species that are able to bind and inhibit several enzymes responsible for the intracellular redox homeostasis, in particular the selenoenzyme thioredoxin reductase. Show less

In this work, we demonstrate bioorthogonal control of the phosphorescence and singlet oxygen photosensitisation properties of new iridium(iii) tetrazine complexes by different reaction partners; the system was exploited for organelle-specific staining and modulated photocytotoxic activity applications. Show less

Fourteen new Ru^II -arene (p-cymene/benzene) complexes (C1-C14) have been synthesized by varying the N-terminal substituent in the furoylthiourea ligand and satisfactorily characterized by using analytical and spectroscopic techniques. Electrostatic potential maps predicted that the electronic effect of the substituents was mostly localized, with some influence seen on the labile chloride ligands. The structure-activity relationships of the Ru-p-cymene and Ru-benzene complexes showed opposite trends. All the complexes were found to be highly toxic towards IMR-32 cancer cells, with C5 (Ru-p-cymene complex containing C₆ H₂ (CH₃ )₃ as N-terminal substituent) and C13 (Ru-benzene complex containing C₆ H₄ (CF₃ ) as N-terminal substituent) showing the highest activity among each set of complexes, and hence they were chosen for further study. These complexes showed different behavior in aqueous solutions, and were also found to catalytically oxidize glutathione. They also promoted cell death by apoptosis and cell cycle arrest. Furthermore, the complexes showed good binding ability with the receptors Pim-1 kinase and vascular endothelial growth factor receptor 2, commonly overexpressed in cancer cells. Show less

The study of cancer metabolism is regaining center stage and becoming a hot topic in tumor biology and clinical research, after a period where such kind of experimental approaches were somehow forgotten or disregarded in favor of powerful functional genomic and proteomic studies [...]. Show less

Scatiltri and colleagues review the paradigms of targeting PI3K in solid tumors in the clinic, including the progress so far in developing effective inhibitors as well as clinical limitations due to toxicity and therapeutic resistance. Show less