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Two Palladium complexes are presented as a promising alternative to platinum drugs disadvantages, controlling the speciation and limiting toxicity. Their interaction vs. biological targets and their efficiency are demonstrated, being more specific than the benchmark cisplatin drug.

Metal compounds form an attractive class of ligands for a variety of nucleic acids. Five metal complexes bearing aminopyridyl-2,2'-bipyridine tetradentate ligands and possessing a quasi-planar geometry were challenged toward different types of nucleic acid molecules including RNA polynucleotides in the duplex or triplex form, an RNA Holliday four-way junction, natural double helix DNA and a DNA G-quadruplex. The binding process was monitored comparatively using different spectroscopic and melting methods. The binding preferences that emerge from our analysis are discussed in relation to the structural features of the metal complexes.

The interaction between the series of berberine derivatives 1–5 (NAX071, NAX120, NAX075, NAX077 and NAX079) and human telomeric G-quadruplexes (G4), which are able to inhibit the Telomerase enzyme’s activity in malignant cells, was investigated. The derivatives bear a pyridine moiety connected by a hydrocarbon linker of varying length (n = 1–5, with n number of aliphatic carbon atoms) to the C13 position of the parent berberine. As for the G4s, both bimolecular 5′-TAGGGTTAGGGT-3′ (Tel12) and monomolecular 5′-TAGGGTTAGGGTTAGGGTTAGGG-3′ (Tel23) DNA oligonucleotides were considered. Spectrophotometric titrations, melting tests, X-ray diffraction solid state analysis and in silico molecular dynamics (MD) simulations were used to describe the different systems. The results were compared in search of structure–activity relationships. The analysis pointed out the formation of 1:1 complexes between Tel12 and all ligands, whereas both 1:1 and 2:1 ligand/G4 stoichiometries were found for the adduct formed by NAX071 (n = 1). Tel12, with tetrads free from the hindrance by the loop, showed a higher affinity. The details of the different binding geometries were discussed, highlighting the importance of H-bonds given by the berberine benzodioxole group and a correlation between the strength of binding and the hydrocarbon linker length. Theoretical (MD) and experimental (X-ray) structural studies evidence the possibility for the berberine core to interact with one or both G4 strands, depending on the constraints given by the linker length, thus affecting the G4 stabilization effect.

A series of bioactive molecules were synthesized from the condensation of aspirin or chlorambucil with terminal alkynes bearing alcohol or amine substituents. Insertion of the resulting alkynes into the iron-carbyne bond of readily accessible diiron bis(cyclopentadienyl) mu-aminocarbyne complexes, [1a,b]CF3SO3, afforded novel diiron complexes with a bridging vinyliminium ligand, [2-10]CF3SO3, functionalized with a bioactive moiety. All compounds were characterized by elemental analysis and IR and multinuclear NMR spectroscopy and in three cases by single-crystal X-ray diffraction. Moreover, the D2O solubility, stability in D2O and cell culture media, and octanol-water partition coefficients of diiron complexes were determined spectroscopically. The cytotoxicity of the complexes was assessed in the tumorigenic A2780 and A2780cisR and the nontumorigenic HEK 293T cell lines. Some complexes exhibit high potency and the ability to overcome resistance in A2780cisR cells (aspirin complexes) or high selectivity relative to HEK 293T cells (chlorambucil complexes). Further studies indicate that the complexes significantly trigger intracellular ROS production, irrespective of the nature of the bioactive fragment. DNA alkylation and protein binding studies were also undertaken.

In this work, we prepared color-changing colloids by using the electrostatic self-assembly approach. The supramolecular structures are composed of a pH-responsive polymeric surfactant and the water-soluble porphyrin 5,10,15,20-tetrakis-(sulfonatophenyl)porphyrin (TPPS). The pH-responsive surfactant polymer was achieved by the chemical modification of an alternating aliphatic polyketone (PK) via the Paal&ndash, Knorr reaction with N-(2-hydroxyethyl)ethylenediamine (HEDA). The resulting polymer/dye supramolecular systems form colloids at the submicron level displaying negative zeta potential at neutral and basic pH, and, at acidic pH, flocculation is observed. Remarkably, the colloids showed a gradual color change from green to pinky-red due to the protonation/deprotonation process of TPPS from pH 2 to pH 12, revealing different aggregation behavior.

AuIII complexes with N‐heterocyclic carbene (NHC) ligands have shown remarkable potential as anticancer agents, yet their fate in vivo has not been thoroughly examined and understood. Reported herein is the synthesis of new AuIII‐NHC complexes by direct oxidation with radioactive [124I]I2 as a valuable strategy to monitor the in vivo biodistribution of this class of compounds using positron emission tomography (PET). While in vitro analyses provide direct evidence for the importance of AuIII‐to‐AuI reduction to achieve full anticancer activity, in vivo studies reveal that a fraction of the AuIII‐NHC prodrug is not immediately reduced after administration but able to reach the major organs before metabolic activation., Images: The reaction of [124/131I]I2 with AuI‐N‐heterocyclic carbene precursors affords a strategy to label AuIII anticancer agents and study their biodistribution in vivo by positron emission tomography.

Metals and metal-based compounds have many implications in biological systems. They are involved in cellular functions, employed in the formation of metal-based drugs and present as pollutants in aqueous systems, with toxic effects for living organisms. Amphiphilic molecules also play important roles in the above bio-related fields as models of membranes, nanocarriers for drug delivery and bioremediating agents. Despite the interest in complex systems involving both metal species and surfactant aggregates, there is still insufficient knowledge regarding the quantitative aspects at the basis of their binding interactions, which are crucial for extensive comprehension of their behavior in solution. Only a few papers have reported quantitative analyses of the thermodynamic, kinetic, speciation and binding features of metal-based compounds and amphiphilic aggregates, and no literature review has yet addressed the quantitative study of these complexes. Here, we summarize and critically discuss the recent contributions to the quantitative investigation of the interactions of metal-based systems with assemblies made of amphiphilic molecules by calorimetric, spectrophotometric and computational techniques, emphasizing the unique picture and parameters that such an analytical approach may provide, to support a deep understanding and beneficial use of these systems for several applications.

Based on the ability of terpyridines to react with G-quadruplex DNA (G4) structures along with the interest aroused by Zn as an essential metal centre in many biological processes, we have synthesized and characterized six Zn chloride or nitrate complexes containing terpyridine ligands with different 4'-substituents. In addition, we have studied their interaction with G4 and their cytotoxicity. Our experimental results revealed that the leaving group exerts a strong influence on the cytotoxicity, since the complexes bearing chloride were more cytotoxic than their nitrate analogues and an effect of the terpyridine ligand was also observed. The thermal stabilization profiles showed that the greatest stabilization of hybrid G4, Tel22, was observed for the Zn complexes bearing the terpyridine ligand that contained one or two methylated 4-(imidazol-1-yl)phenyl substituents, 3Cl and 3(L)2, respectively, probably due to their extra positive charge. Stability and aquation studies for these complexes were carried out and no ligand release was detected. Complexes 3Cl and 3(L)2 were successfully internalized by SW480 cells and they seemed to be localized mainly in the nucleolus. The highest cytotoxicity, G4 selectivity and G4 affinity determined by fluorescence and ITC experiments, and subcellular localization quantified by ICP-MS measurements, rendered 3Cl a very interesting complex from a biological standpoint.

We present here a combined spectroscopic and theoretical analysis of the binding of N,N’-bis(2-(1-piperazino)ethyl)-3,4,9,10-perylenetetracarboxylic acid diimide dichloride (PZPERY) to different biosubstrates. Absorbance titrations and circular dichroism experiments, melting studies and isothermal calorimetry (ITC) titrations reveal a picture where the binding to natural double-stranded DNA is very different from that to double and triple-stranded RNAs (poly(A)∙poly(U) and poly(U)∙poly(A)⁎poly(U)). As confirmed also by the structural and energetic details clarified by density functional theory (DFT) calculations, intercalation occurs for DNA, with a process driven by the combination of aggregates disruption and monomers intercalation. Oppositely, for RNAs, no intercalation but groove binding with the formation of supramolecular aggregates is observed. Among all the tested biosubstrates, the affinity of PZPERY towards DNA G-quadruplexes (G4) is the greatest one with a preference for human telomeric G4s. Focusing on hybrid G4 forms, either sitting-atop (“tetrad-parallel”) or lateral (“groove-parallel”) binding modes were considered in the discussion of the experimental results and molecular dynamics (MD) simulations. Both turned out to be possible concurrently, in agreement also with the experimental binding stoichiometries higher than 2:1., “la Caixa” Foundation (LCF/PR/PR12/11070003), Ministerio de Ciencia, Innovación y Universidades-FEDER (RTI2018-102040-B-100) and Junta de Castilla y León-FEDER (BU305P18). LC acknowledges funding by the European Research Council, under the grant ERC-AdG-786714 (LIFETimeS)

Several complexes of general formula [Ru(halide)(η6-p-cymene)(α-diimine)]+, in the form of nitrate, triflate and hexafluorophosphate salts, including a newly synthesized iodide compound, were investigated as potential anticancer drugs and bactericides. NMR and UV–Vis studies evidenced remarkable stability of the complexes in water and cell culture medium. In general, the complexes displayed strong cytotoxicity against A2780 and A549 cancer cell lines with IC50 values in the low micromolar range, and one complex (RUCYN) emerged as the most promising one, with a significant selectivity compared to the non-cancerous HEK293 cell line. A variable affinity of the complexes for BSA and DNA binding was ascertained by spectrophotometry/fluorimetry, circular dichroism, electrophoresis and viscometry. The performance of RUCYN appears associated to enhanced cell internalization, favored by two cyclohexyl substituents, rather than to specific interaction with the evaluated biomolecules. The chloride/iodide replacement, in one case, led to increased cellular uptake and cytotoxicity at the expense of selectivity, and tuned DNA binding towards intercalation. Complexes with iodide or a valproate bioactive fragment exhibited the best antimicrobial profiles.

This work concerns an analysis of the binding mechanism of a copper phthalocyanine (Alcian Blue-tetrakis(methylpyridinium) chloride, ABTP) to natural calf thymus DNA, G-quadruplexes (G4) and synthetic RNA polynucleotides in the form of double polyriboadenylic·polyribouridylic acid (poly(A)·poly(U)) or triple strands polyriboadenylic·2polyribouridylic acid (poly(A)·2poly(U)). ABTP is a well know dye that might undergo novel applications, but its interaction with DNA is scarcely studied and we lack information on possible RNA or G4 binding. This might be related to system complexity due to the presence of supramolecular dye-dye aggregates. Despite this, we show here that apparent parameters can be calculated, which provide information on the binding mechanism. Absorbance titrations in the presence of biosubstrate excess, melting and circular dichroism experiments show that ABTP binds to both RNAs and DNA. External/groove binding is the main feature for RNAs, whereas partial intercalation is the major binging mode for DNA. ABTP externally binds to both hybrid, parallel and anti-parallel G4s but seem to show a slightly different binding mode and a preference for anti-parallel structures. The thermodynamic features of the different systems are also discussed in the frame of the enthalpy-entropy compensation phenomenon., la Caixa” Foundation (LCF/PR/PR12/11070003), Ministerio de Ciencia, Innovación y Universidades-FEDER (RTI2018- 102040-B-100) and Junta de Castilla y León-FEDER (BU305P18)

The use of Pt(iv) complexes as potential anticancer drugs is attractive, because they have higher stability and less side effects than Pt(ii) compounds. Moreover, some Pt(iv) complexes can also be activated with light, opening an avenue to photochemotherapy. Our purpose is to widen the library of photoactivatable Pt(iv)-based prodrugs and here we report on the oxidation of the Pt(ii) compound [PtCl(4'-phenyl-2,2':6',2''-terpyridine)][CF3SO3] (1) with PhICl2 or H2O2. The synthetic procedure avoids the formation of multiple species: the treatment with PhICl2 produces the Pt(iv) complex with axial chlorides, [PtCl3(4'-phenyl-2,2':6',2''-terpyridine)][CF3SO3] (2), while H2O2 oxidation and post-synthesis carboxylation produce [Pt(OCOCH3)2Cl(4'-phenyl-2,2':6',2''-terpyridine)][CF3SO3] (3), bearing acetates in the axial positions. 2 and 3 are stable in physiological-like buffers and in DMSO in the dark, but undergo photoreduction to 1 upon irradiation at 365 nm. Their stability toward reduction is a fundamental parameter to consider: cyclic voltammetry experiments show that the 2 electron reduction Pt(iv) → Pt(ii) occurs at a more negative potential for 3, because of the greater stabilization provided by the acetate axial groups; noteworthily, 3 is stable for hours also in the presence of mM concentration of glutathione. The cytotoxicity of 2 and 3 toward A2780 and A2780cis cell lines reveals that 3 is the least toxic in the dark, but is able to produce cytotoxic effects far higher than cisplatin when irradiated. To shed light on the mechanistic aspects, the interaction with protein and DNA models has been explored through high-resolution mass spectrometry revealing that 2 and 3 behave as prodrugs, but are able to bind to biological targets only after irradiation.

Au(III) complexes with N-Heterocyclic Carbenes (NHCs) ligands have shown remarkable potential as anticancer agents, yet their fate in vivo has not been thoroughly examined and understood. Herein we report on the synthesis of new Au(III)-NHC complexes via direct oxidation with radioactive [124I]I2 as a valuable strategy to monitor the in vivo biodistribution of this class of compounds using positron emission tomography (PET) and, in combination with in vitro analyses, to provide direct evidence of the importance of Au(III)-to-Au(I) reduction for achieving full anticancer activity.

The equilibria and kinetics of the interaction of In(III) with Alizarin Red S (ALZS) and Methyl Thymol Blue (MTB) dyes in aqueous solution were investigated. Spectrophotometric titrations at different pHs (1.8–2.7 range) revealed that, concerning the In-ALZS system, under conditions of metal excess the prevailing complex is ML, while stopped flow experiments have shown that, in the investigated pH range the kinetics are monophasic although the ML complex is formed through different paths involving both In(H2O)63+ and In(H2O)5(OH)2+ as active species reacting with the monoprotonated ligand (HL). The In-MTB system was studied with the same methodology in the pH range 1.0–2.0. The complex (MH3L) prevails although the above metal species react with differently protonated forms of the ligand. The In-MTB system displays a biphasic kinetic behavior involving a network of reaction steps, where fast pre-equilibria related to metal coordination at the carboxylates/nitrogen site, precedes slow coordination at the phenol/phenol or phenol/quinone sites. The key role in the reaction mechanism is played by the ligand features rather than by the solvent/ligand substitution process.

The solution behavior of auranofin, Et3PAuCl and Et3PAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward representative colorectal cancer cell lines were found to be strong and similar in the three cases and a good correlation could be established between the cytotoxicity and the ability to inhibit thioredoxin reductase; remarkably, in vivo acute toxicity experiments for Et3PAuI confirmed that, similarly to auranofin, this drug is well tolerated in a murine model. Overall, a very similar profile emerges for Et3PAuI and Et3PAuCl, which retain the potent cytotoxic effects of auranofin while showing some peculiar features. These results demonstrate that the presence of the thiosugar moiety is not mandatory for the pharmacological action, suggesting that the tuning of some relevant chemical properties...

To the best of our knowledge this is the first report on the application of induced circularly polarized luminescence (CPL) for sensing the binding of fluorescent dyes to double stranded DNA. Using Thiazole Orange (TO) and 4′,6-diamidino-2-phenylindole (DAPI) as models, we show utility and limitations of CPL in DNA binding studies. The results obtained indicate that CPL can be used as a new chiroptical tool for this purpose, however, special attention while recording CPL data must be used, in order to exclude measurement artefacts caused by linear polarization components.

In this study, we report on the synthesis of new organic fluorophores containing either the p-phenylene or the benzodithiophene cyclic nucleus connected to thiophene units via triple bonds and carbonyl group, and on their application for the fabrication of luminescent solar concentrators (LSCs). Their optical properties were evaluated. Independent of the core, dyes containing the CO-thiophene residues seem to be the most promising for LSCs applications. In fact , carbonyl groups slightly enhance the quantum yield but significantly increase the red-shift of the emission so that the superimposition between the absorbance spectrum and the emission one is diminished. In the case of the benzodithiophene centre, light emission in the yellow-red portion of the spectrum is achieved. The latter dye is then selected for tests in a poly(methyl methacrylate) (PMMA) matrix. It showed good compatibility and homogenous distribution, no auto-absorption phenomena, and optical efficiencies of about 8% at 1 wt. %, i.e. comparable with those PMMA/Lumogen Red films in the same range of concentration.

Regio- and stereoselective nucleophilic attack of cyanide (from NBu4CN) to cationic diiron vinyliminium compounds [Fe2Cp2(CO)(mu-CO){mu-eta(1):eta(3)-C-(R')C(R '')-CNMe2}]CF3SO3 ([1a-f]CF3SO3) affords the nitrile-aminoallylidene derivatives 2a-f in good to excellent yield. The analogous reaction of [1g]CF3SO3, comprising two different N substituents, gives 4 (63%) as a mixture of two stereoisomers. The new products [lg]CF3SO3, 2a-f, and 4 were characterized by IR and NMR spectroscopy and in a number of cases by IR-spectroelectrochemistry and single-crystal X-ray diffraction. The allylidene complexes are air-stable and robust in aqueous solution; however, in general they undergo oxidation within a biologically relevant range of potentials. DFT calculations were carried out to rationalize the observed stereoselectivity of the synthesis reaction and other structural and thermodynamic aspects. The cytotoxicity of 2a-f was assessed on cisplatin-sensitive and -resistant human ovarian carcinoma (A2780 and A2780cisR) cell lines and human embryonic kidney (HEK-293) cells. Experiments reveal that treatment with the compounds leads to ROS production, with an absence of direct interactions with double-stranded DNA (calf thymus) and bovine serum albumin.

The synthesized 2-(hydroxy-1-naphtyl)imidazo-[4,5-f][1,10]phenanthroline (HNAIP) ligand and its new iridium ([Ir(ppy)2(HNAIP)]Cl) and rhodium ([Rh(ppy)2(HNAIP)]Cl) complexes, being ppy = 2-phenylpiridinate, show cytotoxic effects in SW480 (colon adenocarcinoma) and A549 (epithelial lung adenocarcinoma) cells. They all are cytotoxic in the tested cell lines. HNAIP and [Rh(ppy)2(HNAIP)]+ are the most cytotoxic, whereas [Ir(ppy)2(HNAIP)]+ displays negligible cytotoxicity towards A549 cells and moderate activity towards SW480. The interaction of all three compounds with Bovine Serum Albumin (BSA), l-glutathione reduced (GSH), nicotinamide adenine dinucleotide (NADH) and DNA was studied to explain the differences found in terms of cytotoxicity. None of them are able to interact with BSA, thus excluding bioavailability due to plasma protein interaction as the possible differentiating factor in their biological activity. By contrast, small differences have been observed regarding DNA interaction. In addition, taking advantage of the emission properties of these molecules, they have been visualized in the cytoplasmic region of A549 cells. Inductively coupled plasma mass spectrometry (ICP-MS) experiments show, in turn, that the internalization ability follow the sequence [Rh(ppy)2(HNAIP)]+ > [Ir(ppy)2(HNAIP)]+ > cisplatin. Therefore, it seems clear that the cellular uptake by tumour cells is the key factor affecting the different cytotoxicity of the metal complexes and that this cellular uptake is influenced by the hydrophobicity of the studied complexes. On the other hand, preliminary catalytic experiments performed on the photo-oxidation of GSH and some amino acids such as l-methionine (Met), l-cysteine (Cys) and l-tryptophan (Trp) provide evidence for the photocatalytic activity of the Ir(III) complex in this type of reactions., “la Caixa” Banking Foundation (LCF/PR/PR12/11070003), Ministerio de Ciencia, Innovación y Universidades (RTI2018-102040-B-100 and RTI2018-100709-B-C21), Junta de Castilla y León (BU305P18, FEDER Funds)

New pyridinimino complexes of platinum(II) [PtCl2(N^N-R)] (N^N = 2-pyridylmethanimino, R = -(CH2)2O(CH2)2OH, -(CH)2O(CH2)2OCH2Pyr), Pyr = pyren-1-yl) have been prepared. They are characterized by a dioxygenated alkyl side chain and, in one case, by a fluorescent terminal 1-pyrenyl residue. The complexes were characterized by elemental analysis, IR, 1H–, 13C–and 195Pt NMR spectroscopies. For [PtCl2(N^N-(CH2)2O(CH2)2OH] the molecular structure was determined by single crystal X-ray diffraction. The complexes are soluble and stable in DMSO/H2O (80/20, v/v). The pyrenyl terminated compound was tested as antiproliferative agent against selected human cancer cell lines. Comparable cytotoxic effect was obtained on human ovarian carcinoma A-2780 and A-2780cis cells, thus suggesting a certain ability to circumvent cisplatin resistance. The interaction of this complex with DNA was investigated by linear flow dichroism and by spectrophotometric (absorbance and fluorescence) titrations. Both techniques enlightened the presence of a complex mode of interaction with DNA, involving both groove binding and intercalation.

A series of diiron complexes based on the [Fe2Cp2(CO)x] skeleton (Cp = η5-C5H5, x = 2, 3; η4-C5H5Ph in place of one Cp in one case) and containing different bridging hydrocarbyl ligands (aminocarbyne, thiocarbyne, allenyl) were preliminarily investigated for their anticancer potential. The water solubility, stability in water and in the presence of a cell culture medium, and octanol/water partition coefficient were evaluated by spectroscopic techniques. The cytotoxicity was assessed in vitro toward the human ovarian carcinoma cell line A2780, the human triple negative breast cancer cell line MDA-MB-231, and the human vascular smooth muscle cell line SMC. Some aminocarbyne complexes exhibited a potent cytotoxicity, with IC50 values in the low micromolar/nanomolar range, and a strong selectivity for the A2780 cells in comparison to the SMC cell line. Several experiments were carried out in order to give insight into the mode of action of selected compounds, including an assessment of catalytic NADH oxidation and ROS production and studies of binding with DNA and with a model protein.

New luminophores having different aryl nuclei and propynones moieties have been obtained via Sonogashira reactions. Their optical properties were evaluated and indicated that carbonyl groups are responsible for significant bathochromic effects and high Stokes shifts. The insertion of -OMe groups on the central benzene unit gives to the fluorophore high optical efficiency (7.7%) when homogeneously dispersed in a poly(cyclohexyl methacrylate) (PCMA) film and connected to a PV cell.

PubMedID: 31528919 In this work, the interaction between an Auramine O (AuO) fluorescent molecular rotor and natural DNA, its thermodynamic aspects and the resulting variation of the optical properties upon binding are addressed by a combined spectroscopic (UV-vis and fluorescence) and computational approach. DNA binding causes a shift in the maximum of absorption from 432 nm to 444 nm, a decrease of the extinction coefficient and a dramatic enhancement of fluorescence emission, these results being in agreement with intercalation into the polynucleotide helix. Intercalation is indeed confirmed by the thermodynamic parameters for the binding reaction (in particular, the highly negative ?H). Theoretical modelling at the TD-DFT level was done on a simplified model system consisting of the AuO molecule intercalated between two DNA base pairs. The evolution of the calculated vertical transitions quantitatively reproduces the experimentally observed hypo- and bathochromic shifts, thus confirming the intercalation hypothesis. © 2019 the Owner Societies.

A silver(I) and a gold(I) complex of the fluorescent N-heterocyclic carbenic (NHC) ligand 1-(9-anthracenylmethyl)-3-(3-trimethylsilyl-2-propynil)-benzimidazol-2-ylidene have been synthesized and characterized. These compounds show cytotoxicity in the micromolar range and higher antiproliferative properties than cisplatin (CDDP) against several tumour cell lines such as SW480 (colon), A549 (lung) and HepG2 (liver). Both metal complexes are successfully internalized by SW480 cells being the silver compound the most accumulated. Subsequently, they were evaluated as inhibitors of the selenoenzyme Thioredoxin reductase (TrxR) and as DNA binders. Fluorescence microscopy confirmed that both protein and DNA binding could be involved in the biological activity of the compounds. The silver carbene was the most effective enzyme inhibitor with an IC50 in the nanomolar range. Also, interaction studies with natural double stranded DNA highlight a strong stabilisation of the double helix after binding to the Ag(I) carbene, indicating its potential suitability as dual-targeting anticancer active molecule., “la Caixa” Foundation (LCF/PR/PR12/11070003), Ministerio de Ciencia Innovación y Universidades-FEDER (RTI2018-102040-B-100) and Junta de Castilla y León-FEDER (BU305P18).

The synthesized 2-(hydroxy-1-naphtyl)imidazo-[4,5-f][1,10]phenanthroline (HNAIP) ligand and its new iridium ([Ir(ppy)

Metal complexes of N-heterocyclic carbene (NHC) ligands are the object of increasing attention for therapeutic purposes. Among the different metal centres, interest on Au-based compounds started with the application as anti-arthritis drugs. On the other hand, Ag(I) antimicrobial properties have been known for a long time. For Au(I)/Au(III)-NHC and Ag(I)-NHC anti-tumour and anti-proliferative properties have been quite recently demonstrated. In addition to these and as for Group 11, copper is a much less investigated metal centre, but a few papers underline its pharmacological potential. This review wants to focus on the different biological targets for these metal-based compounds. It is divided into chapters which are respectively devoted on: i) mitochondria and thiol oxidoreductase systems; ii) other relevant enzymes; iii) nucleic acids. Examples of representative coinage NHCs for each of the targets are provided together with significant references on recent advances on the topic. Moreover, a final comment summarises the aspects enlightened by each chapter and provides some hints to better understand the metal-NHCs mechanistic behaviour based on structure-activity relationships.

The study of the interaction of persistent organic pollutants with biosubstrates helps to unravel the pathways for toxicity, however, few mechanistic data are present in the literature for these systems. We analyzed the binding of paraquat (PQ) and diquat (DQ) herbicides to natural calf thymus DNA and a DNA G-quadruplex by spectrophotometric titrations, ethidium bromide exchange tests, viscometry, and melting experiments. The interaction with bovine serum albumin (BSA) protein was studied spectrofluorimetrically at different temperatures. The retention of the targets on positive, negative, and neutral micellar aggregates and liposomes was analyzed by ultrafiltration experiments. Despite some favorable features, PQ and DQ only externally bind natural DNA and do not interact with DNA oligonucleotides. Both herbicides bind bovine serum albumin (BSA). PQ binds BSA mainly according to an electrostatics-driven process. However, ultrafiltration data also show that some hydrophobic contribution participates in the features of these systems. The practical problems related to unfavorable spectroscopic signals and inner filter effects are also discussed. Overall, both herbicides show a low affinity for nucleic acids and weak penetration into liposomes, in addition, the equilibrium constants values found for BSA system suggest optimal conditions for transport in the body.

Protein binding heavily modulates drug activity. Therefore, the binding features need to be elucidated when chemistry researchers study new molecules (metal complexes) to be used as drugs. This paper concerns the experimental and data treatment aspects of the mechanistic analysis of the binding to a fluorescent protein (the golden standard serum albumin) by using direct fluorescence titrations. Fluorescence data are not rarely only qualitatively used, neglecting further treatments which could offer a precious detailed picture of the behavior of the drug. We aim to spread a mechanistic approach, discussing the critical aspects for correctly designing the experiments and treating the data. The researcher may confirm adduct formation and evaluate binding constants (Stern-Volmer KSV or other types of K). Also, we discuss here, with the help of literature examples, the correct use of temperature dependence of K to extract thermodynamic parameters, comment on enthalpy-entropy compensation, together with the use of synchronous spectra and exchange experiments to gain information on the binding type and site. We think that this tutorial/critical synopsis can be of help for the increasing community dealing with these experiments, which are valuable but often much more tricky than it might appear at first sight.

We report on the preparation of luminescent collectors based on poly(methyl methacrylate) (PMMA) thin films doped with a red-emitting 2-amino-7-acceptor-9-silafluorene, where the amino group is -N(CH3)(2) and the acceptor is -CH=C(CN)(2). The results obtained from photophysical investigations of the dye in different solvents and in PMMA are very encouraging as the silafluorene dyes turn out to be highly dispersed in the solid matrix, stable upon irradiation and highly emissive. QY and lifetime investigations demonstrate that autoabsorption phenomena moderately occur with SilaFluo content, and the optical features still maintained very significant, also at the highest fluorophore concentration (QY similar to 65%). Study of the LSCs features yields excellent optical efficiencies of 9.6% attained for 25 mm thick PMMA films containing the 1.5 wt% of SilaFluo. This performance is at the top level with respect to the current state-of-art of similar devices based on perylene-based fluorophores such as Lumogen Red.

The PADA/SDS system provides an excellent tool to selectively extract metal ions using the ligand-modified micellar-enhanced ultrafitration (LM-MEUF) technique. Application of this method to the extraction of Au(III) has required a detailed knowledge of the conditions under which the interaction of the metal ion with the extractor are optimal. For this purpose the kinetics and the equilibria of the reaction between tetrachloro-aurate ion and PADA have been investigated in water/SDS medium, exploring wide ranges of pH values and NaCl concentrations. Addition of PADA to the water/SDS medium results in the full adsorption of the ligand on the micelle and, in the presence of Au(III), the resulting Au-PADA complex is fully retained on the SDS surface. The binding process is, in fact, a ligand displacement reaction where PADA interacts with different Au(III) chloro-aquo complexes, displacing Cl- or OH- or H2O molecules, depending on pH. The reaction is biphasic and its mechanism is discussed. Experiments at different SDS concentrations show that the reaction of complex formation is retarded on going from pure water to a water/SDS mixture with [SDS] just above the cmc, while for further increases of the SDS content the reaction rate tends to stay constant. The obtained results enabled to establish that the reaction occurs on the SDS surface while the aquo-species, Au(H2O)Cl3 and Au(OH)3(H2O), which are not involved in the binding process in pure water, play an important kinetic role in the H2O/SDS medium. © 2016. OSLC-2012-007 Financial support by Obra Social La Caixa (OSLC-2012-007) is gratefully acknowledged. Appendix A

The binding to biosubstrates and micellar systems of pollutants as the polycyclic aromatic hydrocarbon (PAH) derivatives 1-aminopyrene (1-PyNH2) and 1-hydroxymethylpyrene (1-PyMeOH) and the carbamate-pesticides 1-naphthyl-N-methylcarbamate (carbaryl, CA) and methyl benzimidazol-2-ylcarbamate (carbendazim, CBZ) was analysed through an integrated strategy combining spectroscopy and quantum chemistry. As biosubstrates, natural DNA and bovine serum albumin (BSA) were taken into account for a thermodynamic analysis of the binding features through spectrophotometric and spectrofluorometric techniques. In all cases, a strong DNA interaction is present and intercalation is supposed as the major binding mode. For the PAH derivatives, DNA binding is found to be favoured under high salt conditions and BSA static quenching and binding with 1:1 stoichiometry occurs. The molecular structure and optical properties of 1-PyNH2, CA and CBZ together with their intercalated adducts in DNA were studied also by means of quantum chemical approach. The (TD)DFT calculations on intercalated dye/DNA adducts quantitatively reproduce the experimentally observed spectroscopic changes, thus confirming the intercalation hypothesis. The theoretical approach also provides information on the adducts' geometries and on the amount of charge transfer with DNA. Moreover, ultrafiltration tests in the presence of anionic (SDS), cationic (DTAC) and neutral (Triton X) micellar aggregates and liposomes provided insights into lipophilicity and cellular membrane affinity. PAH derivatives show high retention coefficient in all cases, whereas in the case of carbamate-pesticides micellar retention might be significantly reduced and is very limited in the case of liposomes.

The bis carbene gold(I) complex [Au(1-butyl-3-methyl-2-ylidene)2]PF6, ([Au(NHC)2]PF6 hereafter), holds remarkable interest as a perspective anticancer agent. The compound is stable under physiological like conditions: its original structure is retained even in the presence of excess glutathione (GSH). Previous studies revealed its high cytotoxicity in vitro that correlates with the impairment of crucial metabolic and enzymatic cellular processes (Magherini et al., Oncotarget, 2018, 9, 28042). Here, the interaction of [Au(NHC)2]PF6 with the human telomeric DNA G-quadruplex Tel23 has been investigated in solution by means of high resolution mass spectrometry. ESI MS experiments well document the formation of stable 1 : 1 adducts between the biscarbene gold complex – in its intact form – and the DNA G-quadruplex Tel23. Next, through independent biophysical methods, we show that [Au(NHC)2]PF6 binding does not significantly affect the G quadruplex melting temperature nor its conformation. The crystal structure for the [Au(NHC)2]+/Tel24 adduct was eventually determined by a joint X-ray diffraction and in silico simulation approach. Through the careful integration of solution and solid-state data, a quite clear picture emerges for the interaction of this gold complex with the Tel23 G-quadruplex.

According to the recent developments in imaging strategies and in tailoring fluorescent molecule as probe for monitoring biological systems, we coupled a Bodipy-based molecular rotor ( BoMe ) with FLIM phasor approach to evaluate the viscosity in different intracellular domains. BoMe rapidly permeates cells, stains cytoplasmic as well as nuclear domains, and its optical properties make it perfectly suited for widely diffused confocal microscopy imaging setups. The capability of BoMe to report on intracellular viscosity was put to the test by using a cellular model of a morbid genetic pathology (Hutchinson–Gilford progeria syndrome, HGPS). Our results show that the nucleoplasm of HGPS cells display reduced viscosity as compared to normal cells. Since BoMe displays significant affinity towards DNA, as demonstrated by an in vitro essay, we hypothesize that genetic features of HGPS, namely the misassembly of lamin A protein within the nuclear lamina, modulates chromatin compaction. This hypothesis nicely agrees with literature data.

Interfacial bioconjugation methods are developed for intact liquid emulsion droplets. Complex emulsion droplets having internal hydrocarbon and fluorocarbon immiscible structured phases maintain a dynamic interface for controlled interfacial reactivity. The internal morphological change after binding to biomolecules is readily visualized and detected by light transmission, which provides a platform for the formation of inexpensive and portable bio-sensing assays for enzymes, antibodies, nucleic acids and carbohydrates.

Microplastics generated by plastics waste degradation are ubiquitous in marine and freshwater basins, posing serious environmental concerns. Raman and FTIR spectroscopies, along with techniques such as pyrolysis-GC/MS, are typically used for their identification. We present a procedure based on gel permeation chromatography (GPC) coupled with fluorescence detection for semi-quantitative selective determination of the most common microplastics found in marine shoreline sediments: poly(styrene) (PS) and partially degraded polyolefins (LDPEox). By operating the detector at either 260/280 or 370/420 nm excitation/emission wavelengths PS can be distinguished from LDPEox upon GPC separation. Semi-quantitative determination of microplastics contents is also possible: dichloromethane extracts of PS and LDPEox yield linear plots of fluorescence peak area vs concentration (0–5.0 mg/mL range) and were used as reference materials for quantification of the microplastics content in sand samples collected in the winter berm and dune sectors of a Tuscany beach in Italy.

A series of donor-π-acceptor (D-π-A) substituted 4-hydroxythiazoles have been synthesized. Electron-donating groups (4-methoxyphenyl and 4-dimethylaminophenyl) were installed in the 5-position of the thiazole; thiophene/pyridine-bridged acceptors (formyl groups and their Knoevenagel condensation products) were placed in the 2-position. The influence of D-π-A character on the photophysical properties and electronic structure was investigated by means of UV/Vis and fluorescence spectroscopy.

A work ( Fraenkel , D. J. Chem. Theory Comput. 2018 , 14 , 2609 , DOI: 10.1021/acs.jctc.7b01260 ) was recently published in which, starting from data of activity coefficients of electrolytes determined by Malatesta and co-workers in the years 1992-2000, an incorrect conclusion is reached, i.e., that the negative deviations from the Debye-Hückel limiting law found at high dilution for high-charge polyvalent electrolytes were presumably not real. The present work shows the reasons why we cannot share his opinion. The negative deviations are supported both by the theory and by experimental demonstration.

The triplatinum complex of the 2,4,6-Tris(2-pyrimidyl)-1,3,5-triazine ligand, Pt 3 TPymT hereafter, has been prepared and characterized for the first time. NMR studies point out that the three platinum(II) centers possess an identical coordination environment. The interactions of Pt 3 TPymT with DNA were explored in comparison to the free ligand. Specifically, fluorescence, mass spectrometry, viscometry and melting measurements were carried out. In contrast to expectations, the obtained data reveal that no intercalative binding takes place; we propose that binding of Pt 3 TPymT to DNA mainly occurs through external/groove binding.

Kinetics of coordination of Pd(II) by the macrocyclic porphyrin 5,10,15,20-tetrakis(1-methyl-4-pyridyl)porphyrin (H2P4+) is investigated and confirms quantitative formation of a planar PdP4+ complex at room temperature (formation rate 0.19 M-1 s-1 at 25 °C, 0.2 M NaCl, pH 3). Then, the binding ability to DNA of the pre-formed PdP4+ complex is analysed. To achieve this aim, spectrophotometry, spectrofluorometry and viscometry are used. Thermodynamic parameters for binding, obtained by the temperature dependence of the equilibrium constants, are ?H = –71 kJ mol-1 and ?S = -134 J mol-1 K-1. These values, being both highly negative, agree with full PdP4+ intercalation into DNA. Moreover, kinetics of the binding reaction is analysed by the T-jump technique (reaction times in the 1–5 ms range). Experiments on the porphyrin ligand retention on negative SDS and positive DTAC micellar surfaces are also done. Taken altogether, these data provide mechanistic details on complex formation and on DNA binding and relevant energies and driving forces. It is found that interaction between PdP4+ and base pairs is very strong (Kabs DNA = 8.0 × 105 M-1 at 25 °C, 1.0 M NaCl), not only owing to the high positive charge borne by the complex, but also to the contribution of high hydrophobicity of the porphyrin ring. In the dye/DNA complex, PdP4+ is buried into the helix, as confirmed also by fluorescence quenching tests. Both presence and type of metal ion play a major role, as lower affinity and lower induced helix conformation changes are found in the case of the H2P4+/DNA and CuP4+/DNA systems. © 2017, Springer-Verlag GmbH Austria. Consejería de Educación, Junta de Castilla y León: BU042U16 PRA_2017_28 OSLC-2012-007 Ministerio de Economía y Competitividad: CTQ2014-58,812-C2-2-R Acknowledgements The financial support by PRA 2017 of the University of Pisa—Project PRA_2017_28, from ‘‘la Caixa’’ Foundation (Project OSLC-2012-007), MINECO—Spain (CTQ2014-58,812-C2-2-R, FEDER Funds) and Junta de Castilla y León (BU042U16, FEDER Funds) is gratefully acknowledged.