Cytotoxicity of Alizarine versus Tetrabromocathecol Cyclometalated Pt(II) Theranostic Agents: A Combined Experimental and Computational Investigation.

Platinum compounds cytotoxicity is strictly related to their ability to be converted into active mono- and di-aquated species and consequently to the replacement of labile ligands by water molecules. This activation process makes the platinum center prone to nucleophilic substitution by DNA purines. In the present work, quantum mechanical density functional theory (DFT) computations and experimental investigations were carried out in order to shed light on the relationship between the internalization, aquation, and DNA binding of two isostructural anionic theranostic complexes previously reported by our group, NBu4[(PhPy)Pt(Aliz)], 1 (IC50 1.9 ± 1.6 µM), and NBu4[(PhPy)Pt(BrCat)], 2 (IC50 52.8 ± 3.9 µM). Cisplatin and a neutral compound [(NH3)2Pt(Aliz)], 3, were also taken as reference compounds. The computed energy barriers and the endergonicity of the hydrolysis reactions showed that the aquation rates are comparable for 1 and 2, with a slightly higher reactivity of 1. The second hydrolysis process was proved to be the rate-determining step for both 1 and 2, unlike for compound 3. The nucleophilic attack by the N7 site of guanine to both mono- and di-aquated forms of the complexes was computationally investigated as well, allowing to rationalize the observed different cytotoxicity. Computational results were supported by photostability data and biological assays, demonstrating DNA as the main target for compound 1.

Photoconductive Properties and Electronic Structure in 3,5-Disubstituted 2-(2'-Pyridyl)Pyrroles Coordinated to a Pd(II) Salicylideneiminate Synthon.

The synthesis and the electrochemical, photophysical, structural, and photoconductive properties of three new heteroleptic Pd(II) complexes with various 3',5'- disubstituted-2-(2'-pyridil) pyrroles H(N^N) as coordinated ligands are reported. The coordination of the metal center was completed by a functionalized Schiff base H(O^N) used as an ancillary ligand. The [(N^N)Pd(O^N)] complexes showed highly interesting photoconductive properties which have been correlated to their electronic and molecular structures. Theoretical density functional theory (DFT) and time-dependent DFT calculations were performed, and the results were confronted with the organization in crystalline phase, allowing to point out that the photoconductive properties are mainly a consequence of an efficient intramolecular ligand-to-metal charge transfer, combined to the proximity between the central metal and the donor moieties in the solid-state molecular stacks. The reported results confirm that these new Pd(II) complexes form a novel class of organometallic photoconductors with intrinsic characteristics suitable for molecular semiconductors applications.

Adsorption of Nile Red Self-Assembled Monolayers on Au(111).

The ability of Nile Red to self-assemble into supramolecular packings on Au(111) was studied using scanning tunneling microscopy and modeled through theoretical semiempirical calculations. At both submonolayer (sub-ML) and ML coverages, two distinct molecular packings, that is, four-leaf clover and dense chain, were observed, both weakly interacting with the underlying metal surface. Theoretical calculations suggested that the dipole moment plays a subtle role in both molecular assemblies, held together by hydrogen bonds between the Nile Red molecules. Furthermore, although both molecular assemblies were observed in as-deposited samples, a mild thermal annealing caused the transition from the four-leaf clover to the dense-chain packing, pointing out the greater stability of the dense-chain configuration. The study further emphasized how the established interactions between the Nile Red molecules are strongly influenced by the surrounding environment.

The potential of the F127-water soft system towards selective solubilisation of iridium(III) octahedral complexes.

In order to obtain new functional soft systems for use as templating agents for the construction of functional mesostructured materials, the dynamic ordered soft systems formed by a hydrophilic ionic iridium(III) complex (IrPa) embedded into two different concentration F127-water mixtures have been investigated. To this aim, combined spectral and time-resolved photophysical techniques and rheological methods have been employed. The position of the chromophore inside the micellar, cubic and hexagonal phases of the F127 polymeric neutral surfactant in water was effectively determined. The hydrophilic character of the iridium(III) complex chosen allowed preferential functionalization of the F127 corona in the micellar and cubic phases.

Electrochromic behaviour of Ir(iii) bis-cyclometalated 1,2-dioxolene tetra-halo complexes: fully reversible catecholate/semiquinone redox switches.

Neutral cyclometalated Ir(iii) complexes of general formula [Ir(ppy)2(O^O)squi], where ppy = 2-phenylpyridine and (O^O)squi = TBC (tetrabromocatechol) or TCC (tetrachlorocatechol) in their semiquinone (squi) monoanionic redox state, were synthesized by chemically oxidizing the anionic parent complexes NBu4[Ir(ppy)2(O^O)cat], in which (O^O)cat represents the corresponding ancillary dioxolene ligand in its dianionic catecholate (cat) redox state. This chemical oxidation leads to the modification of both the photophysical and the magnetic properties of the complexes. While the NBu4[Ir(ppy)2(O^O)cat] complexes are diamagnetic (D) and yellow-orange solids, the corresponding oxidized complexes [Ir(ppy)2(O^O)squi] display paramagnetic (P) properties and are characterized by a dark-green color. The conversion between the two forms (squi vs. cat) is electrochemically and chemically fully reversible. Indeed, the anionic NBu4[Ir(ppy)2(O^O)cat] complexes are quantitatively restored by chemical reduction of the neutral [Ir(ppy)2(O^O)squi] parents. These complexes therefore represent interesting redox based switches between multi-parameter states since they allow switching from a neutral paramagnetic to an anionic diamagnetic form together with a significant change in chromicity. Taking advantage of the significant color difference between the oxidized and the reduced form, an electrochromic cell was prepared with [Ir(ppy)2(TBC)squi] and its spectroelectrochemical properties are reported.

Anionic versus neutral Pt(II) complexes: The relevance of the charge for human serum albumin binding.

The focus of this work is pointing out the different behavior of two structurally related Pt(II) complexes, the anionic cyclometalated NBu4[(Bzq)Pt(Thio)], 1 and the neutral [(Phen)Pt(Thio)], 2, (Bzq = benzo[h]quinoline, Phen = 1,10-phenantroline, Thio = 1,2-benzenedithiolate), on the interaction with human serum albumin (HSA), a key drug-delivery protein in the bloodstream. Being very limited the number of anionic Pt(II) complexes reported to date, this is a pioneering example of report on a protein-ligand interaction involving a negatively charged platinum compound. The study was carried out by using fluorescence spectroscopy, differential scanning calorimetry and molecular docking simulations. The results revealed a strong binding affinity between the anionic compound and the protein, whereas a weak/moderate binding interaction was highlighted for the neutral one. Comparative studies with site specific ligands (warfarin and ibuprofen), allowed us to identify the protein binding sites of the two compounds. The work aims to shed light on the relevance of the charge in designing new drugs with a favorable binding affinity for HSA, which strongly contributes to influence their pharmacological and toxicological profile.

Unsuspected mesomorphism in "tail-free" cyclopalladated 3,5-disubstituted-2-(2'-pyridyl)pyrroles.

The first cyclopalladation of 3,5-disubstituted-2-(2'-pyridyl)pyrroles leads to columnar metallomesogens of non-conventional molecular shape.

Functional properties of metallomesogens modulated by molecular and supramolecular exotic arrangements.

New concepts for the synthesis of metallomesogens have been recently developed in order to use the metal centre as a scaffold for grafting different functionalities and inducing non-conventional shapes and properties in the resulting complexes. Our strategy was based on the synthesis of mesogenic coordination complexes whose molecular architectures are controlled by the modulation of different and tunable molecular motifs: the nature of the metal ion and the surrounding ligands as central unit, the number of flexible chains at the periphery, and the nature of counter-ions in ionic complexes. The appropriate choice of molecular construction motifs allows control at global architectures and induces pre-selected properties from the level of single molecule to supramolecular network, confirming that metal coordination provides a helpful tool for obtaining multifunctional soft materials.

Electropolymerizable IrIII Complexes with ß-Ketoiminate Ancillary Ligands.

A series of electropolymerizable cyclometallated IrIII complexes were synthesized and their electrochemical and photophysical properties studied. The triphenylamine electropolymerizable fragment was introduced by using triphenylamine-2-phenylpyridine and, respectively, triphenylamine-benzothiazole as cyclometalated ligands. The coordination sphere was completed by two differently substituted ß-ketoiminate ligands deriving from the condensation of acetylacetone or hexafluoroacetylacetone with para-bromoaniline. The influence of the -CH3 /-CF3 substitution to the electrochemical and photophysical properties was investigated. Both complexes with CH3 substituted ß-ketoiminate were emissive in solution and in solid state. Highly stable films were electrodeposited onto ITO coated glass substrates. Their emission was quenched by electron trapping within the polymeric network as proven by electrochemical studies. The -CF3 substitution of the ß-ketoiminate leads instead to the quenching of the emission and inhibits electropolymerization.

Light-induced reorientation and birefringence in polymeric dispersions of nano-sized crystals.

Nanocrystals (50-250 nm) of a Palladium complex within a polyisobutylmethacrylate matrix were prepared by a phase separation method. In these dispersions, a light-induced birefringence with Deltan approximately 10(-3) was induced, without the application of an electric field. This effect was related to the photoconducting properties of the dispersion. Evidence for charge photogeneration without any applied field was obtained. The photorefractive behaviour of the material confirmed that the nanocrystals reorientation is a consequence of photoconducting properties. A light-generated electric field approximaely E 3 V/microm was estimated. These results illustrate the potential of materials with a nano-crystalline dispersion morphology as light-responsive media.

A "jellyfish" shaped green emitting gallium(III)-containing metallomesogen.

The synthesis of the first gallium(III)-based liquid crystal has been achieved grafting around the metal centre two chelating 2-methylquinolin-8-olate anions and one monodentate 3,4,5-tris(hexadecyloxy)benzoyloxy ligand, allowing the resulting complex to be a soft luminescent material with the typical high quantum yield of pentacordinated gallium species.

Anionic cyclometalated Pt(ii) and Pt(iv) complexes respectively bearing one or two 1,2-benzenedithiolate ligands.

Novel anionic cyclometalated Pt(ii) square-planar complexes NBu4[(C^N)PtII(S^S)], containing 2-phenylpyridine H(PhPy), 2-(2,4-difluorophenyl)-pyridine H(F2PhPy) and benzo[h]quinoline H(Bzq), respectively, as a cyclometalated ligand and the dianionic 1,2-benzenedithiolate (Thio)2- fragment as an (S^S) ligand, were synthesised. By the simple addition of an equivalent of (Thio)2- to the NBu4[(C^N)PtII(Thio)] complexes, octahedral anionic NBu4[(C^N)PtIV(Thio)2] analogues were obtained, representing, to the best of our knowledge, the first examples of Pt(iv) anionic cyclometalated complexes. The molecular structures of the obtained complexes in the case of the NBu4[(Bzq)PtII(Thio)] and the NBu4[(Bzq)PtIV(Thio)2] complexes were confirmed by single crystal X-ray diffraction analysis. Furthermore, the electrochemical and photophysical properties of the two series of Pt(ii) and Pt(iv) newly synthesised complexes were studied and DFT and TD-DFT calculations were performed in order to comprehensively investigate the displayed behaviour. All Pt(ii) and Pt(iv) complexes show intense luminescence in the solid state, with remarkable enhancement of the emission quantum yields, proving to be excellent examples of aggregation-induced emission systems.

Curcumin and cyclopalladated complexes: a recipe for bifunctional biomaterials.

The first examples of binuclear and mononuclear ortho-palladated complexes based on a functionalized 2-phenylquinoline ligand have been synthesized and fully characterized. Conjugating cyclopalladated fragments to curcumin family biologically active beta-diketones gives in one single molecule two different functionalities. The structural variations based on the curcuminoid structure have been tested for their in vitro cytotoxic activity. The activity of complexes comprised of a cyclopalladated fragment conjugated to functionalized bioactive ligands, represents the potential of organometallic systems in generating new bifunctional biomaterials.

Anionic cyclometallated Pt(ii) square-planar complexes: new sets of highly luminescent compounds.

Two series of novel NBu4+ salts of anionic cyclometallated Pt(ii) complexes were synthesized and fully characterized. These highly luminescent compounds (NBu4[(C^N)Pt(O^N)] and NBu4[(C^N)Pt(O^O)]) are incorporated as testing examples of cyclometallating ligands 2-phenylpyridine (PhPy), 2-(2,4-difluorophenyl)-pyridine (F2PhPy) and 2-thienylpyridine (ThPy), and a benzo[h]quinoline (Bzq) fragment. All complexes display a square-planar coordination sphere, wherein the "(C^N)Pt" fragment is completed either by an O^N orotate (Ort) or an O^O tetrabromocatecholate (Cat) ligand. The HOMO and LUMO levels of all complexes were estimated by cyclic voltammetry and a comprehensive electrochemical and photophysical study was performed. The new complexes are emissive in solution at 298 K and the NBu4[(ThPy)Pt(Ort)] complex displays good photosensitizing properties (Φ = 28% in deaerated solution vs. Φ = 1.4% in the presence of O2). Both series of NBu4[(C^N)Pt(Ort)] and NBu4[(C^N)Pt(Cat)] complexes are highly luminescent in the solid state (emission quantum yields from 10 to 85%). Remarkably, the square-planar Pt(ii) anionic complexes showed an important increase in luminescence quantum yields on changing from the dilute solution to the solid state (the most significant from 0.13% to 85% for the NBu4[(PhPy)Pt(Ort)] complex, an ideal candidate as an active species for LEECs).

High Order in a Self-Assembled Iridium(III) Complex Gelator Towards Nanostructured IrO2 Thin Films.

The preparation and characterization of a new metallogelator based on the IrIII discrete cyclometalated complex [(ppy)2 Ir(bpy)](CH3 CH2 OCH2 CO2 ) are reported, where H(ppy) is 2-phenylpiridine and bpy is 2,2'-bipyridine, which is used as an ancillary ligand. The compound is able to self-assemble in water in a range of concentrations between 3 % and 6 % w/w, creating a luminescent ordered supramolecular gel. The gel and xerogel architectures were investigated through polarized optical microscopy (POM), SEM and TEM microscopies coupled with powder X-ray diffraction. The gel supramolecular organization is characterized by columnar tetragonal strands, already present at high dilution conditions, of cations surrounded by counteranions. These strands, in turn, are self-assembled in an oblique columnar cell upon gelification. The xerogel thin films obtained upon complete dehydration maintained the gel supramolecular order and can be used as a precursor for the preparation of nanostructured IrO2 thin films.

Plasmon-mediated cancer phototherapy: the combined effect of thermal and photodynamic processes.

A nanoplatform for simultaneous cellular imaging, and photodynamic and photothermal therapies has been designed and realized by embedding a purposely synthesized highly luminescent water soluble iridium(iii) compound into gold core-silica shell nanoparticles. These multifunctionalities arise mainly from the photophysical properties of the cyclometalated complex: (i) the heavy atom promotes, through excited triplet state formation, energy transfer processes towards molecular oxygen, with the generation of 1O2 (photodynamic effect); (ii) the overlap of the iridium(iii) complex emission band with the plasmonic resonance of gold nanostructures allows excitation energy transfer towards the metallic core (photothermal effect); (iii) the remarkable iridium(iii) complex luminescence feature, which is preserved despite energy transfer processes, makes the whole system an efficient luminescent bio-probe (imaging). Photophysical and photothermal investigations have been carried out, whereas in vitro photo-cytotoxicity tests have been performed on human glioblastoma cells (U87MG), highlighting significant cancer cell death at a very low photosensitizer concentration (<0.5 µM), by means of a synergistic photodynamic and photothermal effect.

Synthesis and anticancer activity of cyclopalladated complexes containing 4-hydroxy-acridine.

The synthesis and the characterization (elemental analysis, (1)H NMR and X-ray) of the first cyclopalladated complexes containing 4-hydroxyacridinate as complementary ligand are described. 4-Hydroxyacridine acts as a bidentate [N,O] chelating ligand, giving rise to square planar Pd(II) complexes in the coordination of a cyclopalladated fragment of phenylpyridine or phenylpyrimidine, characterized by the presence of two almost coplanar metalated rings. The biological activity studies conducted on these new Pd(II) complexes proved that the phenylpyridine Pd(II) derivative is more efficient than cis-platinum. The intrinsically substitutional inertness of the cyclopalladated ring and the presence of the [N,O] chelated acridine ligand make these systems of particular interest in their promising biological activity.

Near-IR Electrochromism in Electrodeposited Thin Films of Cyclometalated Complexes.

Homogeneous thin films of controlled thickness obtained from cyclometalated complexes of general formula [(C(∧)N)M(O(∧)N)], where M = Pd(II) or Pt(II), H(C(∧)N) = 2-phenylpyridine and, respectively, 2-thienylpyridine and H(O(∧)N) = a triphenylamine functionalized Schiff base, have been deposited by oxidative electropolymerization. The films have been electrochemically and morphologically characterized. The metallopolymeric thin films present stable reversible redox behavior and typical cauliflower-like textures in agreement with a nucleation-growth electropolymerization mechanism. However, the film growth is greatly influenced by the nature of the metal center, with a higher tendency of the Pt complexes to promote the 3D growth. Furthermore, a complete spectroelectrochemical study has been performed on electrodeposited films showing near-IR absorption in the oxidized state, high contrast ratios (up to 65%) and low response times.

A novel route towards water-soluble luminescent iridium(iii) complexes via a hydroxy-bridged dinuclear precursor.

The synthesis and photophysical characterization of a new family of luminescent water-soluble ionic iridium(iii) complexes of the general formula [(ppy)2Ir(bpy)]X are reported. The Ir(iii) complexes incorporate a cyclometalated 2-phenylpyridine (ppy), the ancillary ligand 2,2'-bipyridyl (bpy) and different counterions (X- = EtO-, OH-, EtOCH2CO2-, MeOCH2CO2-). These complexes were obtained starting from the cyclometalated Ir(iii) chloro-bridged dimer [(ppy)2Ir(µ-Cl)]2, for the first time synthesized through a new microwave assisted synthetic procedure, and subsequently converted into the corresponding hydroxy-bridged dimer [(ppy)2Ir(µ-OH)]2. The latter was eventually used as a sole reagent for the synthesis of all the reported complexes by simply varying the nature of the reaction solvent from water to alcohols and glycol ethers. This study demonstrates the versatility of the [(ppy)2Ir(µ-OH)]2 complex as a precursor to water soluble ionic Ir(iii) complexes. Indeed, [(ppy)2Ir(µ-OH)]2 has shown its peculiar chemical reactivity due to both a strong base character and an unexpected oxidative ability towards the alcoholic function of glycol ethers. All the synthesized complexes exhibit, in water solution, an orange emission centred at 606 nm. Moreover, all complexes display the ability to give rise to gel phases in water upon increasing their concentration, and the photophysical study evidenced the various interactions governing the gelification process. The water-solubility of these new luminescent Ir(iii) complexes makes them potentially useful in bio-related systems.

Electropolymerized highly photoconductive thin films of cyclopalladated and cycloplatinated complexes.

The complete characterization of novel electropolymerizable organometallic complexes is presented. These are newly synthesized cyclometalated complexes of general formula (PPy)M(O ∧ N)(n) (H(PPy) = 2-phenylpyridine, M = Pd(II) or Pt(II), H(O ∧ N)(n) = Schiff base). Polymeric thin films have been obtained from these complexes by electropolymerization of the triphenylamino group grafted onto the H(O ∧ N)(n) ancillary ligand. The redox behavior and the photoconductivity of both of the monomers (PPy)M(O ∧ N)(n) and the electropolymerized species have been investigated. The polymeric films of (PPy)M(O ∧ N)(n) have shown a very significant enhancement of photoconductivity when compared to their monomeric amorphous counterparts. The high stability of the obtained films strongly suggests that electropolymerization of cyclometalated complexes represents a viable deposition technique of quality thin films with improved photoconduction properties, hence opening the door to a new class of materials with suitable properties for optoelectronic applications.