Bioactivity of pyridine-2-thiolato-1-oxide metal complexes: Bi(III), Fe(III) and Ga(III) complexes as potent anti-Mycobacterium tuberculosis prospective agents

In the search for new therapeutic tools against tuberculosis and to further address the therapeutic potential of pyridine-2-thiol 1-oxide (Hmpo) metal complexes, two new octahedral [M(III)(mpo)3] complexes, with M = Ga or Bi, were synthesized and characterized in the solid state and in solution. Attempts to crystallize [Ga(III)(mpo)3] in CH2Cl2 led to single crystals of the reaction product [GaCl(mpo)2], where the gallium(III) ion is in a square basis pyramidal environment, trans-coordinated at the basis to two pyridine-2-thiolato 1-oxide anions acting as bidentate ligands through their oxygen and sulfur atoms. The biological activity of the new [M(III)(mpo)3] complexes together with that of the previously reported Fe(III) analogous compound and the pyridine-2-thiol 1-oxide sodium salt (Na mpo) was evaluated on Mycobacterium tuberculosis. The compounds showed excellent activity, both in the standard strain H37Rv ATCC 27294 (pan-susceptible) and in five clinical isolates that are resistant to the standard first-line anti-tuberculosis drugs isoniazid and rifampicin. These pyridine-2-thiol 1-oxide derivatives are promising compounds for the treatment of resistant tuberculosis.

Photo- and redox-active supramolecular systems containing metal complexes

The aim of this Ph.D. project has been the photophysical and photochemical characterization of new photo- and redox-active supramolecular systems. In particular we studied two different classes of compounds: metal complexes and dendrimers. Two different families of bis-cyclometalated neutral Ir(III) complexes are presented and their photophysical properties are discussed. The first family of complexes contains two 2-phenylpyridyl (ppy) or 2-(4,6-difluorophenyl)pyridyl (F2ppy) cyclometalated ligands and an ancillary ligand constituted by a phenol-oxazoline (phox), which can be substituted in the third position with a fluorine group (Fphox). In the second part of this study, we present another family of bis-cyclometalated Ir(III) complexes in which the ancillary ligand could be a chiral or an achiral bis-oxazoline (box). We report on their structural, electrochemical, photophysical, and photochemical properties. Complexes containing phox and Fphox ancillary ligands show blue luminescence with very high quantum yield, while complexes with box ligands do not show particularly interesting photophysical properties. Surprisingly these complexes give an unexpected photoreaction when irradiated with UV light in presence of dioxygen. This photoreaction originates a stable, strong blue emitting and particularly interesting photoproduct. Three successive generations of a family of polyethyleneglycol (PEG)-coated Pd(II) tetrabenzoporphyrin (PdTBP)-based dendritic nanoprobes are presented, and their ability to sensitize singlet oxygen and inflict cellular photodamage are discussed. It was found that the size of the dendrimer has practically no effect on the singlet oxygen sensitization efficiency, that approximate the unity, in spite of the strong attenuation of the triplet quenching rate with an increase in the dendrimer generation. Nevertheless, when compared against a commonly used singlet oxygen sensitizer, as Photofrin, the phosphorescent probes were found to be non-phototoxic. The lack of phototoxicity is presumably due to the inability of PEGylated probes to associate with cell surfaces and/or penetrate cellular membranes. The results suggest that protected phosphorescent probes can be safely used for oxygen measurements in biological systems in vivo. A new family of two photoswitchable (G0(Azo) and G1(Azo)) dendrimers with an azobenzene core, two cyclam units as coordination sites for metal ions, and luminescent naphthalene units at the periphery have been characterized and their coordination abilities have been studied. Because of their proximity, the various functional groups of the dendrimer may interact, so that the properties of the dendrimers are different from those exhibited by the separated functional units. Both the naphthalene fluorescence and the azobenzene photoisomerization can be observed in the dendrimer, but it has been shown that (i) the fluorescent excited state of the naphthalene units is substantially quenched by excimer and exciplex formation and by energy transfer to the azobenzene units, and (ii) in the latter case the fluorescence quenching is accompanied by the photosensitized isomerization of the trans → cis, and, with higher efficiency, the cis → trans reaction. Complexation of these dendrimers, both trans and cis isomers, with Zn(II) ions shows that complexes of 1:1 and 2:1 metal per dendrimer stoichiometry are formed showing different photophysical and photochemical properties compared to the corresponding free ligands. Practically unitary efficiency of the sensitized isomerization of trans → cis and cis → trans reaction is observed, as well as a slight increase in the naphthalene monomer emission. These results are consistent with the coordination of the cyclam amine units with Zn(II), which prevents exciplex formation. No indication of a concomitant coordination of both cyclam to a single metal ion has been obtained both for trans and cis isomer.

Luminescent Ionic Transition-Metal Complexes for Light-Emitting Electrochemical Cells

The European Union set the ambitious target of reducing energy consumption by 20% within 2020. This goal demands a tremendous change in how we generate and consume energy and urgently calls for an aggressive policy on energy efficiency. Since 19% of the European electrical energy is used for lighting, considerable savings can be achieved with the development of novel and more efficient lighting systems. In this thesis, accomplished in the frame of the EU project CELLO, I report some selected goals we achieved attempting to develop highly efficient, flat, low cost and flexible light sources using Light-Emitting Electrochemical Cells (LECs), based on ionic cyclometalated iridium(III) complexes. After an extensive introduction about LECs and solid-state lighting in general, I focus on the research we carried out on cyclometalated iridium(III) complexes displaying deep-blue emission, which has turned out to be a rather challenging task. In order to demonstrate the wide versatility of this class of compounds, I also report a case in which some tailored iridium(III) complexes act as near-infrared (NIR) sources. In fact, standard NIR emitting devices are typically expensive and, also in this case, LECs could serve as low-cost alternatives in fields were NIR luminescence is crucial, such as telecommunications and bioimaging. Since LECs are based on only one active material, in the last chapter I stress the importance of an integrated approach toward the right selection of suitable emitters not only from the photophysical, but also from the point of view of material science. An iridium(III) complex, once in the device, is interacting with ionic liquids, metal cathodes, electric fields, etc. All these interactions should be taken in to account if Europe really wants to implement more efficient lighting paradigms, generating light beyond research labs.

New functionalized ligands for luminescent metal complexes: from design to applications

The synthesis of luminescent metal complexes is a very challenging task since they can be regarded as the starting point for a lot of different areas. Luminescent complexes, in fact, can be used for technological, industrial, medical and biological applications. During my PhD I worked with different metals having distinguishing intrinsic properties that make them different from each other and, in particular, more or less suitable for the different possible uses. Iridium complexes show the best photophysical properties: they have high quantum yields, very long lifetimes and possess easily tunable emissions throughout the visible range. On the other hand, Iridium is very expensive and scarcely available. The aim of my work concerning this metal was, therefore, to synthesize ligands able not only to form luminescent complexes, but also able to add functionalities to the final complex, increasing its properties, and therefore its possible practical uses. Since Re(I) derivatives have been reported to be suitable as probes in biological system, and the use of Re(I) reduces the costs, the synthesized bifunctional ligands containing a pyridine-triazole and a biotin unit were employed to obtain new Re(I) luminescent probes. Part of my work involved the design and synthesis of new ligands able to form stable complexes with Eu(III) and Ce(III) salts, in order to obtain an emission in the range of visible light: these two metals are quite cheap and relatively non-toxic compared to other heavy metals. Finally, I plan to synthesize organic derivatives that already possessed an emission thanks to the presence of other many chromophoric groups and can be able to link the Zinc (II), a low cost and especially non-toxic “green” metal. Zinc has not its own emission, but when it sticks to ligands, it increases their photophysical properties.

Synthesis and metal complexes of C2 symmetric ligands obtained from (R)-(+)-Betti and dialdehydes for asymmetric induction reactions

The aim of this master’s research thesis was the employment of an enantiopure 1,3-aminoalcohol, the 1-(α-aminobenzyl)-2-naphthol, known as Betti base, for the synthesis of some novel compounds which show a C2 symmetry. Some of these compounds, after derivatization, were used as ligands in association with transition metals to prepare some catalysts for enantioselective catalytic reactions. Some aminoalcohol (Salan-type) derivatives of these compounds were obtained upon reduction and in some cases it was possible to obtain complexes with transition metals such as Mn, Ni, Co and Cu. Furthermore a novel 6-membered analogue bisoxazoline ligand, 2,6-bis((R)-1-Phenyl-1H-naphtho[1,2-e][1,3]oxazin-3-yl)pyridine, was obtained and from it two Cu-complexes were prepared. The metal complexes were employed in some reactions to test the asymmetric induction, which was in some cases up to discrete values.

Structural Studies of Transition Metal Complexes with 4,5-Bis(2-pyridylmethylsulfanyl)-4‘,5‘-ethylenedithiotetrathiafulvalene: Probing Their Potential for the Construction of Multifunctional Molecular Assemblies

Three divalent transition metal complexes of 4,5-bis(2-pyridylmethylsulfanyl)-4‘,5‘-ethylenedithiotetrathiafulvalene have been prepared and crystallographically characterized. The isostructural Co(II) and the Ni(II) complexes show octahedral geometries around the metal ions with the coordination sites occupied by the pyridyl nitrogen atoms and the thioether sulfur atoms of the ligand and cis coordination of the halide ions. Cyclic voltammetry reveals that the complexation leads to a small anodic shift in the first oxidation potential of the TTF system.

Solvation-Driven Charge Transfer and Localization in Metal Complexes

In any physicochemical process in liquids, the dynamical response of the solvent to the solutes out of equilibrium plays a crucial role in the rates and products: the solvent molecules react to the changes in volume and electron density of the solutes to minimize the free energy of the solution, thus modulating the activation barriers and stabilizing (or destabilizing) intermediate states. In charge transfer (CT) processes in polar solvents, the response of the solvent always assists the formation of charge separation states by stabilizing the energy of the localized charges. A deep understanding of the solvation mechanisms and time scales is therefore essential for a correct description of any photochemical process in dense phase and for designing molecular devices based on photosensitizers with CT excited states. In the last two decades, with the advent of ultrafast time-resolved spectroscopies, microscopic models describing the relevant case of polar solvation (where both the solvent and the solute molecules have a permanent electric dipole and the mutual interaction is mainly dipole−dipole) have dramatically progressed. Regardless of the details of each model, they all assume that the effect of the electrostatic fields of the solvent molecules on the internal electronic dynamics of the solute are perturbative and that the solvent−solute coupling is mainly an electrostatic interaction between the constant permanent dipoles of the solute and the solvent molecules. This well-established picture has proven to quantitatively rationalize spectroscopic effects of environmental and electric dynamics (time-resolved Stokes shifts, inhomogeneous broadening, etc.). However, recent computational and experimental studies, including ours, have shown that further improvement is required. Indeed, in the last years we investigated several molecular complexes exhibiting photoexcited CT states, and we found that the current description of the formation and stabilization of CT states in an important group of molecules such as transition metal complexes is inaccurate. In particular, we proved that the solvent molecules are not just spectators of intramolecular electron density redistribution but significantly modulate it. Our results solicit further development of quantum mechanics computational methods to treat the solute and (at least) the closest solvent molecules including the nonperturbative treatment of the effects of local electrostatics and direct solvent−solute interactions to describe the dynamical changes of the solute excited states during the solvent response.

Coinage Metal Complexes as Chiral Catalysts for 1,3-Dipolar Cycloadditions

In this account, we describe the experience of our research group in the implementation of chiral coinage metal complexes into the efficient enantioselective 1,3-DC of azomethine ylides derived from α-amino acids and azlactones with different dipolarophiles. The corresponding chiral metallodipoles were generated in situ and next focused on the synthesis of highly substituted prolines. For this purpose, privileged ligands such as phosphoramidites and binap with silver(I), gold(I) and copper(II) salts are described. Depending from the ligand and mainly from the metal salt it can be possible to control the facial endo/exo-diasteroselectivity and the enantioselectivity of these types of processes. The synthetic processes are also supported by DFT calculations in order to elucidate the most plausible mechanism and the stereochemical results.

Transition metal complexes as mediator-titrants in protein redox potentiometry

A selection of nine macrocyclic Fe-III/II and Co-III/II transition metal complexes has been chosen to serve as a universal set of mediator-titrants in redox potentiometry of protein samples. The potential range spanned by these mediators is approximately from +300 to -700 mV vs the normal hydrogen electrode, which covers the range of most protein redox potentials accessible in aqueous solution. The complexes employed exhibit stability in both their oxidized and their reduced forms as well as pH-independent redox potentials within the range 6 < pH < 9. The mediators were also chosen on the basis of their very weak visible absorption maxima in both oxidation states, which will enable (for the first time) optical redox potentiometric titrations of proteins with relatively low extinction coefficients. This has previously been impractical with organic mediators, such as indoles, viologens and quinones, whose optical spectra interfere strongly with those of the protein.