José Vidal-Gancedo

Design, selection, and characterization of thioflavin-based intercalation compounds with metal chelating properties for application in Alzheimer's disease.

Metal chelation is considered a rational therapeutic approach for interdicting Alzheimers amyloid pathogenesis. At present, enhancing the targeting and efficacy of metal-ion chelating agents through ligand design is a main strategy in the development of the next generation of metal chelators. Inspired by the traditional dye Thioflavin-T, we have designed new multifunctional molecules that contain both amyloid binding and metal chelating properties. In silico techniques have enabled us to identify commercial compounds that enclose the designed molecular framework (M1), include potential antioxidant properties, facilitate the formation of iodine-labeled derivatives, and can be permeable through the blood-brain barrier. Iodination reactions of the selected compounds, 2-(2-hydroxyphenyl)benzoxazole (HBX), 2-(2-hydroxyphenyl)benzothiazole (HBT), and 2-(2-aminophenyl)-1H-benzimidazole (BM), have led to the corresponding iodinated derivatives HBXI, HBTI, and BMI, which have been characterized by X-ray diffraction. The chelating properties of the latter compounds toward Cu(II) and Zn(II) have been examined in the solid phase and in solution. The acidity constants of HBXI, HBTI, and BMI and the formation constants of the corresponding ML and ML2 complexes [M = Cu(II), Zn(II)] have been determined by UV-vis pH titrations. The calculated values for the overall formation constants for the ML2 complexes indicate the suitability of the HBXI, HBTI, and BMI ligands for sequestering Cu(II) and Zn(II) metal ions present in freshly prepared solutions of beta-amyloid (Abeta) peptide. This was confirmed by Abeta aggregation studies showing that these compounds are able to arrest the metal-promoted increase in amyloid fibril buildup. The fluorescence features of HBX, HBT, BM, and the corresponding iodinated derivatives, together with fluorescence microscopy studies on two types of pregrown fibrils, have shown that HBX and HBT compounds could behave as potential markers for the presence of amyloid fibrils, whereas HBXI and HBTI may be especially suitable for radioisotopic detection of Abeta deposits. Taken together, the results reported in this work show the potential of new multifunctional thioflavin-based chelating agents as Alzheimers disease therapeutics.

Shaping Supramolecular Nanofibers with Nanoparticles Forming Complementary Hydrogen Bonds

Functionalized gold nanoparticles with complementary H-bonding groups can control the secondary structure of xerogel fibers formed by a molecular conductor thanks to their incorporation into the nanowires, which show metal-like conductivity once doped without the need for annealing. The picture shows a photograph of the xerogel, TEM images of Au particles in the gel and a single fiber, and an AFM image revealing the texture of the gel.

Tunneling versus Hopping in Mixed-Valence Oligo-p-phenylenevinylene Polychlorinated Bis(triphenylmethyl) Radical Anions

Radical anions 1(-•)-5(-•), showing different lengths and incorporating up to five p-phenylenevinylene (PPV) bridges between two polychlorinated triphenylmethyl units, have been prepared by chemical or electrochemical reductions from the corresponding diradicals 1-5 which were prepared using Wittig-Horner-type chemistry. Such radical anions enabled us to study, by means of UV-vis-NIR and variable-temperature electron spin resonance spectroscopies, the long-range intramolecular electron transfer (IET) phenomena in their ground states, probing the influence of increasing the lengths of the bridges without the need of using an external bias to promote IET. The temperature dependence of the IET rate constants of mixed-valence species 1(-•)-5(-•) revealed the presence of two different regimes at low and high temperatures in which the mechanisms of electron tunneling via superexchange and thermally activated hopping are competing. Both mechanisms occur to different extents, depending on the sizes of the radical anions, since the lengths of the oligo-PPV bridges notably influence the tunneling efficiency and the activation energy barriers of the hopping processes, the barriers diminishing when the lengths are increased. The nature of solvents also modifies the IET rates by means of the interactions between the oligo-PPV bridges and the solvents. Finally, in the shortest compounds 1(-•) and 2(-•), the IET induced optically through the superexchange mechanism can also be observed by the exhibited intervalence bands, whose intensities decrease with the length of the PPV bridge.

Different nature of the interactions between anions and HAT(CN)6: from reversible anion-π complexes to irreversible electron-transfer processes (HAT(CN)6 = 1,4,5,8,9,12-hexaazatriphenylene).

We report experimental evidence indicating that the nature of the interaction established between HAT(CN)(6), a well-known strong electron acceptor aromatic compound, with mono- or polyatomic anions switches from the almost exclusive formation of reversible anion-π complexes, featuring a markedly charge transfer (CT) or formal electron-transfer (ET) character, to the quantitative and irreversible net production of the anion radical [HAT(CN)(6)](•-) and the dianion [HAT(CN)(6)](2-) species. The preferred mode of interaction is dictated by the electron donor abilities of the interacting anion. Thus, weaker Lewis basic anions such as Br(-) or I(-) are prone to form mainly anion-π complexes. On the contrary, stronger Lewis basic F(-) or (-)OH anions display a net ET process. The ET process can be either thermal or photoinduced depending on the HOMO/LUMO energy difference between the electron donor (anion) and the electron acceptor (HAT(CN)(6)). These ET processes possibly involve the intermediacy of anion-π complexes having strong ET character and producing an ion-pair radical complex. We hypothesize that the irreversible dissociation of the pair of radicals forming the solvent-caged complex is caused by the reduced stability (high reactivity) of the radical resulting from the anion.

Radical para-Benzoic Acid Derivatives: Transmission of Ferromagnetic Interactions through Hydrogen Bonds at Long Distances

Investigation of the transmission of magnetic interactions through hydrogen bonds has been carried out for two different benzoic acid derivatives which bear either a tert-butyl nitroxide (NOA) or a poly(chloro)triphenylmethyl (PTMA) radical moiety. In the solid state, both radical acids formed dimer aggregates by the complementary association of two carboxylic groups though hydrogen bonding. This association ensured that atoms with most spin density are separated from one another by more than 15 A. Thus, no competing through-space magnetic exchange interactions are expected in these dimers and, hence, they provide good models to investigate whether noncovalent hydrogen bonds play a role in the long-range transmission of magnetic interactions. The nature of the magnetic exchange interaction and their strengths within similar dimer aggregates in solution was assessed by electron spin resonance (ESR) spectroscopy. In the case of radical NOA, low-temperature ESR experiments showed a weak ferromagnetic interaction between the two radicals in the dimer aggregates (which have the same geometry as in the solid state). In contrast, the corresponding solution ESR study performed with radical PTMA did not lead to any conclusive results, as aggregates were formed by noncovalent interactions other than hydrogen bonds. However, the bulkiness of the poly(chloro)triphenylmethyl radical prevented interdimer contacts in the solid state between regions of high spin density. Hence, solid-state measurements of the alpha phase of PTMA radical provided evidence of the intradimer interaction to confirm the transmission of a weak ferromagnetic interaction through the carboxylic acid bridges, as found for the NOA radical. Moreover, crystallization of the PTMA radical in presence of ethanol to form the beta phase of PTMA radical prevented the dimer formation; this resulted in the suppression of this interaction and provides further evidence of the magnetic exchange mechanism through noncovalent hydrogen bonds at long distances.

Self-assembled monolayers of electroactive polychlorotriphenylmethyl radicals on Au(111).

Two new polychlorotriphenylmethyl (PTM) derivatives bearing a thioacetate and a disulfide group have been synthesized to anchor on gold substrate. On the basis of these molecules, three strategies were followed to prepare self-assembled monolayers (SAMs) of electroactive PTMs. The resulting SAMs were fully characterized by contact angle, atomic force microscopy (AFM), and time-of-flight secondary ion mass spectroscopy (ToF-SIMS). The high coverage surface and stability of the SAMs were demonstrated by cyclic voltammetry. In addition, the electrochemical experiments proved that these SAMs are bistable since it is possible to reversibly switch between the PTM radical state to the corresponding anion. The magnetic response was investigated by electron paramagnetic resonance. We observed that when the PTM SAMs are in their radical form they confer magnetic functionality to the surface, whereas when they are in the anionic state, the surface is diamagnetic. Thus, the PTM-modified substrates are multifunctional surfaces since they combine magnetic and electroactive properties. The reported results show the high potential of these materials for the fabrication of surface molecular devices.

Intra- and Intermolecular Charge Transfer in Aggregates of Tetrathiafulvalene-Triphenylmethyl Radical Derivatives in Solution

An extensive investigation of aggregation phenomena occurring in solution for a family of electron donor-acceptor derivatives, based on polychlorotriphenylmethyl radicals (PTM) linked via a vinylene-bridge to tetrathiafulvalene (TTF) units, is presented. A large set of temperature and/or concentration dependent optical absorption and electron spin resonance (ESR) spectra in a solution of dyads bearing different number of electrons and/or with a hydrogenated PTM residue offer reliable information on the formation of homo dimers and mixed valence dimers. The results shed light on the reciprocal influence of intramolecular electron transfer (IET) within a dyad and the intermolecular charge transfer (CT) occurring in a dimer between the TTF residues and are rationalized based on a theoretical model that describes both interactions.

Induced Self-Assembly of a Tetrathiafulvalene-Based Open-Shell Dyad through Intramolecular Electron Transfer†

An organic switch: An open-shell dyad, consisting of an electron acceptor perchlorotriphenylmethyl radical unit linked to an electron π-donor tetrathiafulvalene unit through a vinylene π-bridge, was synthesized (see picture). The self-assembly of the dyad in solution induced by its intramolecular electron transfer was studied.

Highly Reduced Double-Decker Single-Molecule Magnets Exhibiting Slow Magnetic Relaxation

F64Pc2Ln (1Ln, Ln = Tb or Lu) represent the first halogenated phthalocyanine double-decker lanthanide complexes, and 1Tb exhibits single-molecule magnet properties as revealed by solid-state magnetometry. The fluorine substituents of the phthalocyanine rings have a dramatic effect on the redox properties of the F64Pc2Ln complexes, namely, a stabilization of their reduced states. Electrochemical and spectroelectrochemical measurements demonstrate that the 1Tb(-/2-) and 1Tb(2-/3-) couples exhibit redox reversibility and that the 1Tb(-), 1Tb(2-) and 1Tb(3-) species may be prepared by bulk electrolysis in acetone. Low-temperature MCD studies reveal for the first time magnetization hystereses for the super-reduced dianionic and trianionic states of Pc2Ln.

A New Photomagnetic Molecular System Based on Photoinduced Self‐Assembly of Radicals

An irreversible trans→cis isomerization of the imino group occurs during the irradiation of the new ferrocenyl Schiff-base polychlorotriphenylmethyl radical 1 by light. Low-temperature ESR investigations of frozen solutions revealed that the cis isomer exists as the (cis-1)2 dimer with strong antiferromagnetic interactions. The radical 1 constitutes an example of a one-way photoswitchable magnetic system in which a conversion between a doublet and a singlet ground-state species is promoted by a photoinduced self-assembly process driven by the formation of hydrogen bonds.