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Cyclophanes of different ring sizes featuring perylene-3,4:9,10-tetracarboxylic acid bisimide (PBI) linked by flexible malonates were designed, synthesized, and investigated with respect to their structural, chemical and photo-physical properties. It is predominantly the number of PBIs and their geometric arrangement, which influence dramatically their properties. For example, two-PBI containing cyclophanes reveal physico-chemical characteristics that are governed by strong co-facial π–π interactions. This is in stark contrast to cyclophanes with either three or four PBIs. Key to co-facial π–π stackings are the flexible malonate linkers, which, in turn, set up the ways and means for diastereoselectivity of the homochiral PBIs at low temperatures, on one hand. In terms of selectivity, diastereomeric (M,M)/(P,P) : (M,P)/(P,M) pairs with a ratio of approximately 10 : 1 are discernible in the 1H NMR spectra in C2D2Cl4 and a complete diastereomeric excess is found in CD2Cl2. On the other hand, symmetry-breaking charge transfer as well as charge separation at room temperature are corroborated in steady-state and time-resolved photo-physical investigations. Less favourable are co-facial π–π stackings in the three-PBI containing cyclophanes. For statistical reasons, the diastereoisomers (M,M,M)/(P,P,P) and (M,M,P)/(P,P,M) occur here in a ratio of 1 : 3. In this case, symmetry-breaking charge transfer as well as charge separation are both slowed down. The work was rounded-off by integrating next to the PBIs, for the first time, hydrophobic or hydrophilic fullerenes into the resulting cyclophanes. Our novel fullerene–PBI cyclophanes reveal unprecedented diastereoselective formation of homochiral (M,M)/(P,P) pairs exceeding the traditional host–guest approach. Hybridization with fullerenes allows us to modulate the resulting solubility, stacking, cavity and chirality, which is of tremendous interest in the field., Perylene bisimide (PBI) cyclophanes linked by flexible malonates were functionalized with fullerenes. Modulation of the chemical environment enhances the chiral self-sorting, leading exclusively to the homochiral diastereomeric pair (M,M)/(P,P).

Amongst the different existing methods to passivate black phosphorus (BP) from environmental degradation, the noncovalent functionalization with perylene diimides (PDI) has been postulated as one of the most promising routes because it allows preserving its electronic properties. This work describes the noncovalent functionalization and outstanding environmental protection of BP with tailor made PDI having peri-amide aromatic side chains, which include phenyl and naphthyl groups, exhibiting a significantly increased molecule-BP interaction. These results are rationalized by density functional theory (DFT) calculations showing that the adsorption energies are mainly governed by van der Waals (vdW) interactions and increase concomitantly with the aromatic character of the side chains. The resulting hybrids are thoroughly characterized showing enhanced ambient and thermal stabilities. Last but not least, hybrid organic-inorganic BP-PDI field effect transistors (FETs) are studied for the first time showing the usefulness of PDI derivatives as efficient passivation layers while obtaining improved values of electron mobilities. These results pave the way for the use of optimized PDIs by molecular engineering to preserve the electronic properties of BP FETs, using straightforward wet chemical approaches.

The synthesis and characterization of a new type of a highly conjugated heterocyclic π‐chromophore, consisting of a central triphenylene core fused with three perylene monoimide units (star‐shaped molecules), is described. By judicious bay functionalization with tert‐butylphenoxy substituents, aggregation was completely prevented by using 1,1,2,2‐tetrachloroethane, allowing for a straightforward purification and, for the very first time, the complete separation of the constitutional isomers by HPLC. Both isomers can be easily distinguished by means of several conventional spectroscopic techniques. Furthermore, we have illustrated the absence of supramolecular aggregates and enhanced processability by noncovalent functionalization of graphene substrates, showing an outstanding homogeneity and demonstrating a different doping behavior in both isomers, making it possible to distinguish them by Raman spectroscopy.

[EN] A photoactive bathymeter based on a carboxylic acid moiety covalently linked to a signalling methoxynaphthalene (MNP) fluorophore has been designed to prove the concept of "snorkelling" vs. "diving" in mixed micelles (MM). The carboxylic acid "floats" on the MM surface, while the MNP unit sinks deep in MM. The rate constants of MNP fluorescence quenching by iodide, which remains basically in water, consistently decrease with increasing spacer length, revealing different regions. This is associated with the distance MNP should "dive" in MM to achieve protection from aqueous reactants. Unequivocal proof of the exergonic photoinduced electron transfer was obtained from the UV-visible spectral signature of I-3(-) upon steady-state photolysis. The applicability of the bathymeter was examined upon testing a family of MNP derivatives. The obtained results were validated by comparison with different lipophilicity tests: (i) a modified version of the K-ow partition coefficient and (ii) the retention factor on thin layer chromatography. This concept could potentially be extended to test drugs or pharmacophores exhibiting any photoactive moiety., Financial support from the Spanish Government (SEV-2016-0683), Red RETICS de Investigacion de Reacciones Adversas a Alergenos y Farmacos (RIRAAF), Instituto de Salud Carlos III (RD012/0013, RD16/0006/0030, FIS PI16/01877), VLC-Campus and the Generalitat Valenciana (Prometeo Program) is gratefully acknowledged.

We report a straightforward chemical methodology for controlling the thickness of black phosphorus flakes down to the monolayer limit by layer-by-layer oxidation and thinning, using water as solubilizing agent., We report a straightforward chemical methodology for controlling the thickness of black phosphorus flakes down to the monolayer limit by layer-by-layer oxidation and thinning, using water as solubilizing agent. Moreover, the oxidation process can be stopped at will by two different passivation procedures, namely the non-covalent functionalization with perylene diimide chromophores, which prevents the photooxidation, or by using a protective ionic liquid layer. The obtained flakes preserve their electronic properties as demonstrated by fabricating a BP field-effect transistor (FET). This work paves the way for the preparation of BP devices with controlled thickness.

Single-walled carbon nanotubes (SWCNT) have been covalently cross-linked via a reductive functionalization pathway, utilizing negatively charged carbon nanotubides (KC4). We have compared the use of difunctional linkers acting as molecular pillars between the nanotubes, namely, p-diiodobenzene, p-diiodobiphenyl, benzene-4,4'-bis(diazonium), and 1,1'-biphenyl-4,4'-bis(diazonium) salts as electrophiles. We have employed statistical Raman spectroscopy (SRS), a forefront characterization tool consisting of thermogravimetric analysis coupled with gas chromatography and mass spectrometry (TG-GC-MS) and aberration-corrected high-resolution transmission electron microscopy imaging series at 80 kV to unambiguously demonstrate the covalent binding of the molecular linkers. The present study shows that the SWCNT functionalization using iodide derivatives leads to the best results in terms of bulk functionalization homogeneity (Hbulk) and degree of addition. Phenylene linkers yield the highest degree of functionalization, whereas biphenylene units induce a higher surface area with an increase in the thermal stability and an improved electrochemical performance in the oxygen reduction reaction (ORR). This work illustrates the importance of molecular engineering in the design of novel functional materials and provides important insights into the understanding of basic principles of reductive cross-linking of carbon nanotubes.

The photophysical and photochemical behavior of (R)-cinacalcet (CIN) and (S)-naproxen (NPX) entrapped within liposomes has been studied. For this purpose, liposome encapsulated drugs have been prepared through thin layer evaporation and characterized by transmission electron microscopy, cryoscopy scanning electron microscopy and dynamic light scattering. Steady state and time-resolved fluorescence experiments showed similar spectra, emission quantum yields, singlet energies and lifetimes for the selected drugs, outside and inside liposomes. By contrast, laser flash photolysis experiments revealed an important enhancement of the triplet lifetimes for entrapped drugs inside liposomes, indicating the spatial confinement existing in the microenvironment prevailing in these biomimetic entities. Thus, this photophysical property shows potential as a non-invasive, direct and valuable tool to monitor encapsulation of photoactive drugs and to probe the intraliposome environment. In addition, it provides a new quantitative indicator of the capability of liposomes to act as drug carriers., We gratefully acknowledge financial support from the Carlos III Institute of Health (Servet Contract CP11/00154 for I.A. and Red RETICS de investigacion de Reacciones Adversas a Alergenos y Farmacos, RIRAAF) and from Ministero dell'Istruzione, dell'Universita e della Ricerca (M.I.U.R. Italy).

8 p.-7 fig.1 tab., Triflusal is a platelet aggregation inhibitor chemically related to acetylsalicylic acid, which is used for the prevention and/or treatment of vascular thromboembolisms, which acts as a prodrug. Actually, after oral administration it is absorbed primarily in the small intestine, binds to plasma proteins (99%) and is rapidly biotransformed in the liver into its deacetylated active metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB). In healthy humans, the half-life of triflusal is ca. 0.5 h, whereas for HTB it is ca. 35 h. From a pharmacological point of view, it is interesting to note that HTB is itself highly active as a platelet anti-aggregant agent. Indeed, studies on the clinical profile of both drug and metabolite have shown no significant differences between them. It has been evidenced that HTB displays ability to induce photoallergy in humans. This phenomenon involves a cell-mediated immune response, which is initiated by covalent binding of a light-activated photosensitizer (or a species derived therefrom) to a protein. In this context, small proteins like ubiquitin could be appropriate models for investigating covalent binding by means of MS/MS and peptide fingerprint analysis. In previous work, it was shown that HTB forms covalent photoadducts with isolated lysine. Interestingly, ubiquitin contains seven lysine residues that could be modified by a similar reaction.With this background, the aim of the present work is to explore adduct formation between the triflusal metabolite and ubiquitin as model protein upon sunlight irradiation, combining proteomic and photophysical (fluorescence and laser flash photolysis) techniques. Photophysical and proteomic analysis demonstrates monoadduct formation as the major outcome of the reaction. Interestingly, addition can take place at any of the +-amino groups of the lysine residues of the protein and involves replacement of the trifluoromethyl moiety with a new amide function. This process can in principle occur with other trifluoroaromatic compounds and may be responsible for the appearance of undesired photoallergic side effects., Financial supportfromtheGeneralitatValenciana(Prometeo Program), the Spanish Government (MINECOCTQ2015-70164- P toVL-Vand SAF2012-36519 to DP-S) and the Carlos III Institute of Health(Grant RIRAAF,RETIC Sprogram, RD12/0013/0009 to MM and RD12/0013/0008 to DP-S,and Miguel Servet Contract CP11/00154forIA) is gratefully acknowledged.

New photoactive dyads have been synthesized by derivatization of cholic acid (CA) or cholesterol (Ch). These compounds have proven to be efficient tools to monitor incorporation of CA and Ch to mixed micelles (MM) and to probe the microenvironment experienced inside these entities. The outstanding capability of MM to solubilize Ch has been demonstrated., We gratefully acknowledge financial support from the Generalitat Valenciana (Prometeo Program), the Spanish Government (Red RETICS de Investigacion de Reacciones Adversas a Alergenos y Farmacos (RIRAAF), Servet Contract CP11/00154 for I.A.; CTQ2009-13699 CTQ2010-14882 and Predoctoral FPU fellowship AP2008-03295 for M.G.-M.).

The two enantiomers of the nonsteroidal antiinflammatory drug naproxen and of its methyl ester have been selected as representative probes with markedly different hydrophobicity to assess the potential of cholic acid aggregates as drug carriers by means of photophysical techniques. The different distribution of the probes between bulk solution and aggregates has been assessed by quenching of their singlet and triplet excited states by iodide and nitrite anions, respectively. This straightforward photophysical methodology can, in principle, be extended to a variety of drugs containing a photoactive chromophore. © 2012 American Chemical Society., We gratefully acknowledge financial support from the Generalitat Valenciana (GV/2009/104 and Prometeo Program 2008/090), the Spanish Government (Red RETICS de Investigacion de Reacciones Adversas a Alergenos y Farmacos (RIRAAF)), CTQ2009-13699 and Predoctoral FPU fellowship AP2008-03295 for M. G.-M.).

[EN] Photoinduced processes with partial (exciplex) and full charge transfer in donor-acceptor systems are of interest because they are frequently used for modeling drug-protein binding. Low field photo-CIDNP (chemically induced dynamic nuclear polarization) for these processes in dyads, including the drug, (S)-and (R)-naproxen and (S)-N-methyl pyrrolidine in solutions with strong and weak permittivity have been measured. The dramatic influence of solvent permittivity on the field dependence of the N-methyl pyrrolidine H-1 CIDNP effects has been found. The field dependences of both (R, S)-and (S, S)-dyads in a polar medium are the curves with a single extremum in the area of the S-T+ terms intersection. Moreover, the CIDNP field dependences of the same protons measured in a low polar medium present curves with several extrema. The shapes of the experimental CIDNP field dependence with two extrema have been described using the Green function approach for the calculation of the CIDNP effects in the system without electron exchange interactions. The article discusses the possible causes of the differences between the CIDNP field dependence detected in a low-permittivity solvent with the strong Coulomb interactions and in a polar solvent., This study was supported by the grant 14-03-00-192 of the Russian Foundation of Basic Research. The authors are also deeply grateful to Professor Hans-Martin Vieth for the given opportunity to conduct experiments on his unique equipment.

[EN] Novel diastereomeric triads containing two naphthalene chromophores have been designed in which an electron-donating amine moiety is covalently integrated into the connecting bridge. Photophysical studies (steady-state and time-resolved fluorescence) in solvents of different polarity have been performed. A remarkable stereodifferentiation in the intramolecular fluorescence quenching was found in acetonitrile. Laser flash photolysis gave rise to naphthalene-derived radical cations, which were also quenched by the amine with an even higher degree of stereodifferentiation. The results are in agreement with thermodynamic estimations and indicate that photoinduced electron transfer (PET) is the main quenching pathway. Furthermore, theoretical calculations have allowed us to explain the experimentally observed stereodifferentiation in PET quenching., Financial support from the Generalitat Valenciana (Prometeo Program), the Carlos III Institute of Health (Grant RIRAAF, RETICS program, Miguel Servet Contract CP11/00154 for I. A.), and the Spanish government for the provision of the "Severo Ochoa" excellence project (SEV 2012-0267) is gratefully acknowledged. G.S. thanks ASIC-UPV for computing time.

The influence of chirality on the elementary processes triggered by excitation of the (S,S)- and (R,S)- diastereoisomers of naproxen-pyrrolidine (NPX-Pyr) dyads has been studied by time-resolved fluorescence in acetonitrile-benzene mixtures. In these systems, the quenching of the 1NPX-Pyr singlet excited state occurs through electron transfer and exciplex formation. Fluorescence lifetimes and quantum yields revealed a significant difference (around 20%) between the (S,S)- and (R,S)- diastereomers. In addition, the quantum yields of exciplexes differed by a factor of 2 regardless of solvent polarity. This allows us to suggest a similar influence of the chiral centers on the local charge transfer resulting in exciplex and full charge separation that leads to ion-biradicals. A simplified scheme is proposed to estimate a set of rate constant values (k1-k5) for the elementary stages in each solvent system. © 2013 American Chemical Society., We thank Dr. I. P. Pozdnyakov (Institute of Chemical Kinetics and Combustion SB RAS) and Dr. P. S. Sherin (International Tomography Center SB RAS) for the help with fluorescence measurements. The work was supported by the Russian Foundation for Fundamental Research (grants 11-03-01104, 11-03-92605-KO, 11-03-00268, 12-03-00482), the Program of Integration Projects of SB RAS (grants 33, 88), and the grant of Priority Programs of the RAS (nr. 5.1.5). Financial support from the Generalitat Valenciana (Prometeo Program), the Spanish Government (Red RETICS de Investigacion de Reacciones Adversasa Alergenos y Farmacos (RIRAAF), and CTQ2012-38754-C03-03) is gratefully acknowledged.

Photophysical techniques, specifically time-resolved fluorescence and laser flash photolysis, have proven to be noninvasive, straightforward, and valuable tools to demonstrate how drug encapsulation into biomimetic mixed micelles (MM) influences the dynamics of excited states and their accessibility to ionic quenchers. This concept has been illustrated by choosing a set of currently administered drugs containing a common naphthalene chromophore, namely, (S)-naproxen and its methyl ester, (R)-cinacalcet and (S)-propranolol. A remarkable increase of their triplet lifetimes is noticed when experiments are performed in MM, indicating efficient entrapment of the drugs in these supramolecular entities. Furthermore, a decrease of 1 order of magnitude in the quenching rate constant of the singlet and triplet excited states (by iodide or nitrite, respectively) is observed upon encapsulation into MM. This approach can in principle be extended to other microenvironments capable of incorporating photoactive compounds. © 2013 American Chemical Society., Financial support from the Generalitat Valenciana (Prometeo Program), the Spanish Government (Red RETICS de Investigacion de Reacciones Adversas a Alergenos y Farmacos (RIRAAF), Servet Contract CP11/00154 for I.A., CTQ2009-13699, CTQ2010-14882, CTQ2012-38754-C03-03 and Pre-doctoral FPU fellowship AP2008-03295 for M.G.-M.) is gratefully acknowledged.

Nuin Pla, NE. (2013). PROPIEDADES FOTOQUIMICAS DE FARMACOS QUE CONTIENEN EL CROMOFORO NAFTALENO EN MEDIOS MICROHETEROGENEOS [Tesis doctoral no publicada]. Universitat Politècnica de València. doi:10.4995/Thesis/10251/29753., Alfresco

A new direct and noninvasive methodology based on transient absorption spectroscopy has been developed to probe the feasibility of drug-drug interactions within a common protein binding site. The simultaneous presence of (R)-cinacalcet (CIN) and (S)-propranolol (PPN) within human or bovine alpha(1)-acid glycoproteins (AAGs) is revealed by detection of (CIN)-C-3* as the only transient species after laser flash photolysis of CIN/PPN/AAG mixtures at 308 nm. This is the result of triplet-triplet energy transfer from (PPN)-P-3* to CIN, which requires close contact between the two drugs within the same biological compartment. Similar results are obtained with nabumetone and CIN as donor/acceptor partners. This new methodology can, in principle, be extended to a variety of drug/drug/biomolecule combinations., Financial support from the Spanish Government (CTQ2009-13699, CTQ2010-14882) and from the Carlos III Institute of Health (Grant RIRAAF, RETICS program, and Miguel Servet Contract CP11/00154 for I.A.) is gratefully acknowledged.

Fluoroquinolones (FQs) are photoreactive drugs, but it is not known whether laboratory light exposure can influence the induction of photoproducts and modify in vitro test results. The basophil activation test (BAT) has proven to be useful for evaluating immunoglobulin E (IgE)-mediated hypersensitivity to FQs, with a higher percentage of positive responders with ciprofloxacin (CIP) than with moxifloxacin (MOX). We studied the effect of laboratory light on CIP and MOX degradation, and drug-protein conjugate formation, and its influence on the BAT for evaluating IgE-mediated hypersensitivity to FQs. The results showed an important decrease in fluorescence emission intensity under light compared to dark conditions for MOX, and that BAT positivity was lower in light (17.9%) than in dark (35.7%) conditions. No changes were found for CIP in either fluorescence emission intensity or BAT results (46.4% in both conditions). We can conclude that light exposure is a critical factor in BAT results when photolabile drugs like MOX are used. Therefore, light is important when interpreting in vitro results. Copyright (C) 2012 S. Karger AG, Basel, We thank Ian Johnstone for his help with the English language version of the manuscript, and Jose Luis Rodriguez-Bada and Lidia Melendez for their technical support. This study was funded by the FIS-Thematic Networks and Co-operative Research Centres: RIRAAF (RD07/0064) and the Spanish Health Ministry (FIS PS09/01768, PI11/01416 and M Servet contract CP11/00154 for I.A.), the Andalusia Health Ministry (PI-0545-2010), and the Andalusia Economic Innovation and Science Ministry (CTS 06603).

[EN] The intramolecular electron transfer in the naproxen-N-methylpyrrolidine dyad has been investigated by spin chemistry methods. The existence of CIDNP in a high magnetic field points to electron transfer as a possible mechanism of the quenching of the excited state of a dyad. However, the failure to detect magnetic field effects on triplet yield makes us conclude that this quenching mechanism is not the only one. The observation of CIDNP effects in the dyad in the media of low polarity and the short risetime of triplet state formation indicate a potential role of exciplex in the quenching of the excited state of the dyad., This work was supported by the Grants 08-03-00372 and 11-03-01104 of Russian Foundation of Basic Research, and the grant of Priority Programs of RAS, No. 5.1.5.

[EN] Three drugs containing the naphthalene (NP) chromophore, namely, naproxen (NPX), propranolol (PPN), and cinacalcet (CIN), but with different affinities toward serum albumins (SAs) and alpha-1-acid glycoproteins (AAGs) have been employed for the assessment of drug distribution in binary SA/AAG systems. These three drugs represent an appropriate choice for checking whether a methodology based on transient absorption spectroscopy of a given reporter can be employed for discrimination between different distribution patterns in multicompartmental biological media. Thus, upon laser flash photolysis (LFP) of NPX, PPN, and CIN in the presence or absence of proteins, the NP triplet excited state ((NP)-N-3*) at similar to 420 nm was always detected, although the kinetics of the decay traces was structure- and medium-dependent. In aerated PBS, only a very short triplet lifetime (tau(T)) was found (1-2 mu s). By contrast, in the presence of SAs, two longer triplet lifetimes (5-76 mu s) were observed, ascribed to (NP)-N-3* within site land site II. Upon binding to AAGs, only a long tau(T) (15-47 mu s) was found. When the two proteins were present simultaneously in the same media, fitting of the decay traces was clearly consistent with a distribution of the drug between the different biological compartments and the bulk solution, which correlates well with the known protein affinities of every drug. Experiments were performed in both human (HSA/HAAG) and bovine protein media (BSA/BAAG). The results showed that SAs are the major carriers for NPX; by contrast, PPN binds preferentially to AAGs. An intermediate situation was found for CIN, which presents comparable affinity for both proteins. The results obtained for the two enantiomers of each drug were very similar, although a small stereodifferentiation was observed between the triplet lifetimes in the protein binding sites., Financial support from the MICINN (Grants CTQ2007-67010 and CTQ2010-14882), from the Generalitat Valenciana (Prometeo Program, Ref 2008/090), from Fundacion Cajamurcia, and from Carlos III Institute of Health (Grant RIRAAF, RETICS program) is gratefully acknowledged.

Cinacalcet (CIN) is a calcimimetic drug, which contains a naphthalene chromophore and binds almost quantitatively to human serum albumin (HSA). In the present work, the excited states of CIN have been characterized in order to obtain relevant information about complexation of CIN with HSA. The fluorescence spectrum in acetonitrile, at lambda(exc) = 290 nm, displayed two bands with maxima at 332 and 439 nm, assigned to the monomer and exciplex emission. Upon protonation of the amino group, the exciplex band disappeared, with a concomitant increase of the monomer emission intensity. Time-resolved fluorescence evidenced an intramolecular dynamic quenching, attributed to exciplex formation and/or photoinduced electron transfer, in agreement with the favorable thermodynamics predicted by the Rehm-Weller equations. Diffusion controlled dynamic quenching of CINH(+) fluorescence by oxygen was observed. The emission properties in PBS were similar to those obtained for CINH(+) in acetonitrile. Laser flash photolysis (LFP) of CIN and CINH(+) in aCetonitrile/N(2), at lambda(exc) = 308 nm, gave rise to the naphthalene-like triplet excited states, with maxima at 420 nm and lifetimes of 4 and 7 mu s; they were efficiently quenched by oxygen. No significant singlet excited state interaction was observed in CINH(+)/HSA complexes, as revealed by the emission spectra, which were roughly explained taking into account the relative contributions of drug and protein in the absorption spectra. Upon LFP of the complexes, triplet excited states were generated; the decays monitored at 420 nm were satisfactorily fitted using a function containing two monoexponential terms, corresponding to a Short-lived (tau(1) = 8 mu s) and a long-lived (tau(2) = 37 mu s) component. This indicates that the drug is incorporated into two different binding sites of HSA. Despite the long triplet lifetimes of the CINH(+)/HSA complexes, the rate constant of quenching by oxygen was found to be 2 orders of magnitude lower than that determined in acetonitrile, which can be attributed to the relative slower diffusion rates in this microheterogeneous system. Therefore, the protein microenvironment protects cinacalcet from attack by oxygen; this prevents the phototoxic effects caused by formation of singlet oxygen and results in an enhanced photosafety of the drug., Financial support from the MICINN (Grant CTQ2007-67010), from the Generalitat Valenciana (Prometeo Program, ref 2008/090) and from Carlos III Institute of Health (Grant RIRAAF, RETICS program) is gratefully acknowledged.