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Two symmetric quadrupolar cationic push-pull compounds with a central electron-acceptor (N+-methylpyrydinium, A+) and different lateral electron-donors, (N,N-dimethylamino and N,N-diphenylamino, D) in a D-π-A+-π-D arrangement, were investigated together with their dipolar counterparts (D-π-A+) for their excited-state dynamics and NLO properties. As for the quadrupolar compounds, attention was focused on excited-state symmetry breaking (ESSB), which leads to a relaxed dipolar excited state. Both electron charge displacements and structural rearrangements were recognized in the excited-state dynamics of these molecules by resorting to femtosecond-resolved broadband fluorescence up-conversion experiments and advanced data analysis, used as a valuable alternative approach for fluorescent molecules compared to time-resolved IR spectroscopy, only suitable for compounds bearing IR markers. Specifically, intramolecular charge transfer (ICT) was found to be guided by ultrafast inertial solvation, while diffusive solvation can drive the twisting of lateral groups to originate twisted-ICT (TICT) states on a picosecond time scale. Yet still, only the bis-N,N-diphenylamino-substituted compound undergoes ESSB, in both highly and sparingly polar solvents, provided that it can experience large amplitude motions to a fully symmetry-broken TICT state. Besides well-known solvation effects, this structural requirement proved to be a necessary condition for these quadrupolar cations to undergo ESSB. In fact, a more efficient uncoupling between the out-of-plane D and A+ groups in the TICT state allows a greater stabilization gained through solvation, relative to the bis-N,N-dimethylamino-substituted derivative, which instead maintains its symmetry. This different behavior parallels the two-photon absorption (TPA) ability, which is greatly enhanced in the case of the bis-N,N-diphenylamino-substituted compound, paving the way for cutting-edge bio-imaging applications.

Four newly-synthetized styryl-phenanthroline derivatives were found to exhibit great acidochromism starting from neutral pH values down to negative H0. The aqueous solution of all of the four molecules features a yellow color at nearly neutral pH, but when the acidity of the solution increases, the color changes and, depending on the compound, an orange, pink, purple or colorless hue is observed. Spectrophotometric and fluorimetric titrations were performed to describe the changes in the spectral properties of the molecules with pH. The huge acidochromic shifts shown by these molecules come from the protonation of the nitrogen atoms of the central phenanthroline rings or those of the dimethylamino or diphenylamino side substituents. Thanks to 1H NMR titrations, quantum-mechanical calculations and femtosecond-resolved excited state absorption, a full characterization of the differently protonated forms in terms of protonation sites, spectral and photophysical properties, is reported. These features thus make the molecules' chromophores suitable candidates for applications as acidochromic probes.

Cardiovascular diseases (CVDs) account for over 17 million death globally each year, including arterial thrombosis. Platelets are key components in the pathogenesis of this disease and modulating their activity is an effective strategy to treat such thrombotic events. Cyclooxygenase-1 (COX-1) isoenzyme is involved in platelet activation and is the main target of non-steroidal anti-inflammatory drugs (NSAIDs) and new selective inhibitor research. Inhibitors of general formula mofezolac-spacer-mofezolac (mof-spacer-mof) and mofezolac-spacer-arachidonic acid (mof-spacer-AA) were projected to investigate the possible cross-talk between the two monomers (Eallo and Ecat) forming the COX-1 homodimer. Mofezolac was chosen as either one or two moieties of these molecules being the known most potent and selective COX-1 inhibitor and administrated to humans as Disopain™, then arachidonic acid (AA) was used to develop molecules bearing, in the same compound, in addition to the inhibitor moiety (mofezolac) also the natural COX substrate. Depending on the nature of the spacer, COX-1 and COX-2 activity was differently inhibited by mof-spacer-mof set with a preferential COX-1 inhibition. The highest COX-1 selectivity was exhibited by the compound in which the spacer was the benzidine [N,N’-(biphenyl-4,4′-di-yl)bis (2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamide) (15): COX-1 IC50 = 0.08 μM, COX-2 IC50 > 50 μM, Selectivity Index (SI) > 625]. In the case of mof-spacer-AA set, the COX inhibitory potency and also the isoform preference changed. (5Z, 8Z, 11Z, 14Z)-N-(4-{2-[3,4-Bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}butyl)icosa-5,8,11,14-tetraenamide (19) and (5Z, 8Z, 11Z, 14Z)-N-(4’-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}-[1,1′-biphenyl]-4-yl)icosa-5,8,11,14-tetraenamide (21), in which the spacer is the 1,2-diaminobutane or benzidine, respectively, selectively inhibited the COX-2, whereas when the spacer is the 1,4-phenylendiamine [(5Z, 8Z, 11Z, 14Z)-N-(4-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}phenyl)icosa-5,8,11,14-tetraenamide) (20) the COX preference is COX-1 (COX-1 IC50 = 0.05 μM, COX-2 IC50 > 50 μM, with a COX-1 selectivity > 1000). Molecular modelling by using FLAP algorithm shows fundamental interactions of the novel compounds at the entry channel of COX and inside its catalytic cavity. The effect of these mof-spacer-mof and mof-spacer-AA in inhibiting in vitro free arachidonic acid-induced platelet aggregation was also determined. A positive profile of hemocompatibility in relation to their influence on the blood coagulation cascade and erythrocyte toxicity was observed. Cytotoxicity and genotoxicity safety were also found for these two novel sets of compounds.

In this investigation, we report the first hyperpolarizabilities and two-photon absorption cross sections of a large series of 12 push–pull cationic chromophores. All of these dyes show a dipolar acceptor+–π–donor structure, where the nature of the donor and acceptor units and π-bridge was synthetically tuned to allow insightful comparisons among the molecules. The hyperpolarizability was obtained through a solvatochromic method, by exploiting the rare negative solvatochromism exhibited by the investigated compounds. The two-photon absorption cross sections were determined through two-photon excited fluorescence measurements by means of a tunable nanosecond laser system for sample excitation. The nonlinear optical properties were discussed relatively to the photoinduced intramolecular charge transfer occurring in these donor–acceptor systems, investigated by femtosecond transient absorption experiments. We found a strong increase in hyperpolarizability upon increasing the molecular conjugation. Unexpectedly, the hyperpolarizability is almost unaffected by an increase in donor/acceptor strength and intramolecular charge transfer degree. Differently, the two-photon absorption cross sections of these dyes are enhanced by an increase in both molecular conjugation and intramolecular charge transfer efficiency. Several recent literature works have reported at the same time scattered information about the hyperpolarizability and two-photon absorption of small organic molecules. Our investigation is, to the best of our knowledge, the first attempt to uncover detailed structure–property relationships for these two nonlinear optical properties. Our results represent a promising route to achieve large hyperpolarizability and two-photon absorption in push–pull dyes and may drive the design of new efficient nonlinear optical materials.

We synthetized and characterized a mono spermine porphyrin derivative by NMR, UV-vis and fluorescence spectroscopy. The photophysical properties and the protonation equilibria of 5-(4-carboxyphenylspermine)-10,15,20-triphenylporphyrin have been investigated, showing that porphyrin does not aggregate in acidic solutions, differently from what occurs as soon as the core of the porphyrin is deprotonated. These aggregation processes have been detected by the rising of new fluorescence band and a significant splitting of the Soret band.

The capability of three quaternized styryl-azinium iodides to bind cellular RNA has been tested by means of Fluorescence Confocal Microscopy imaging of stained MCF-7 cells treated with RNase. Their association constants have been estimated through spectrophotometric and fluorimetric titrations with tRNA and compared to their affinity toward DNA. Transient absorption spectroscopy with femtosecond resolution confirmed the binding of the investigated compounds with tRNA and shed new light on the excited state dynamics of their complexes, by revealing a significant lengthening of the lifetime of S1 upon complexation, which parallels the fluorescence quantum yield enhancement.

Six water-soluble bications, characterized by a symmetric A+-π-D-π-A+ structure, were synthesized and comprehensively studied for their absorption and fluorescence properties, and their nonlinear optical response. Generally, the photobehavior exhibited by the six systems was found to be dependent on the molecular dimensionality and conjugation, unveiling the role of different electron-donor (dimethoxy-phenylene vs bithiophene) and electron-acceptor (methyl-pyridinium, methyl-quinolinum, and pyrimidin-pyridinium) substituents bound in different positions (ortho/para). Steady-state measurements revealed this series as a panchromatic family of dyes with noticeable absorption and emission abilities, covering the entire visible spectrum - from the near-ultraviolet to the near-infrared spectral region. Femtosecond-resolved spectroscopy disclosed the presence of ultrafast intramolecular charge transfer processes, as also predicted by TD-DFT calculations, from the central electron-rich moiety of the molecule towards the two lateral positively charged units. Further and for the first time, a solvatochromic method was successfully applied to this kind of quadrupolar double-charged compounds in order to estimate their static and dynamic second-order hyperpolarizability coefficients. Thanks to their appreciable fluorescence capability, significant Two-Photon Absorption cross-sections were also measured for all six dyes by means of the Two-Photon Excited Fluorescence technique. These findings, together with their good water solubility, designate these eye-catching fluorophores as potential candidates for bioimaging applications.

The widespread use of antibiotics has led to a gradual increase in drug-resistant bacterial infections, which severely weakens the clinical efficacy of antibacterial therapies. In recent decades, stilbenes aroused great interest because of their high bioavailability, as well as for their manifold biological activity. Our research efforts are focused on synthetic heteroaromatic stilbene deriva-tives as they represent a potentially new type of antibiotic with a wide antibacterial spectrum. Herein, a preliminary molecular modeling study and a versatile synthetic scheme allowed us to define eight heteroaromatic stilbene derivatives with potential antimicrobial activity. In order to evaluate our compound’s activity spectrum and antibacterial ability, Minimum Inhibitory Con-centration (MIC) and Minimum Bactericidal Concentration (MBC) tests have been performed on Gram-positive and Gram-negative ATCC strains. Compounds PB4, PB5, PB7 and PB8 showed the best values in terms of MIC and were also evaluated for MBC, which however was found to be greater than MIC, confirming a bacteriostatic activity. For all compounds, we evaluated toxici-ty on colon-rectal adenocarcinoma cells tumor cells (CaCo2), once established that the whole se-lected set was more active than 5-Fluorouracil in reducing CaCo-2 cells viability. To the best of our knowledge, the biological assays have shown for these derivatives an excellent bacteriostatic activity, compared to similar molecular structures previously reported, thus paving the way for a new class of antibiotic compounds.

The diarylisoxazole molecular scaffold is found in several NSAIDs, especially those with high selectivity for COX-1. Here, we have determined the structural basis for COX-1 binding to two diarylisoxazoles: mofezolac, which is polar and ionizable, and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) that has very low polarity. X-ray analysis of the crystal structures of COX-1 bound to mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole allowed the identification of specific binding determinants within the enzyme active site, relevant to generate structure/activity relationships for diarylisoxazole NSAIDs.

The ground and excited state properties of 1-methyl-2-[(E)-2-(2-naphthyl) vinyl]pyridinium iodide have been investigated in solvents of different polarities and viscosities using stationary and ultrafast time resolved spectroscopic techniques supported by density functional theory (DFT) calculations. The investigated compound shows an important negative solvatochromism, which serves as evidence of a certain push-pull character exhibited upon photoexcitation, but the most remarkable feature is an extremely large absorption spectrum, as opposed to the narrower emission band. Interestingly, both experiments and calculations have revealed a conformational disorder in the ground state between four quasi-isoenergetic rotamers which contribute to the broad absorption spectrum. These equilibria are shifted towards one prevailing species in the excited state, pointing out an unexpected and efficient rotamer interconversion during the S1 lifetime, manifestly against the non-equilibrated excited rotamers principle. The rotamer interconversion has been found to be very fast and only hindered in a rigid matrix at low temperatures.

Biomarkers of specific targets are becoming an essential objective for clinical unmet clinical needs to improve diseases early detection and increase patient overall survival. Ovarian cancer is among the highest mortality gynecological cancers. It is asymptomatic and almost always diagnosed at advanced stage. At five years from the first diagnosis the survival rate of ovarian cancer patients is only 30%. Cyclooxygenase (COX)-1 as opposed to COX-2 is known to be overexpressed in ovarian cancer. Therefore, fluorescent probes targeting COX-1 were designed and prepared in fair to good yields for its quantitatively detection in human ovarian cancer cell lines (OVCAR-3 and SKOV-3). In particular, both cytofluorimetric and immunofluorescent experiments showed that N-[4-(9-dimethylimino-9H-benzo[a]phenoxazin-5-ylamino)butyl]-2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetamide chloride (11) enters into OVCAR-3 cells and is mainly localized on the membrane containing the COX-1. Membrane fluorescence emission represents about 80% of the total fluorescence measured in the whole cell, while the non-specific labeling represents only 20%. This result indicates that the intensity of fluorescence emission is almost exclusively attributable to 11 bound to COX-1 located on the membrane. Furthermore, no diffusion inside the cell occurs. IC50 hCOX-1 value of 11 determined by measuring the O2 consumption during the bis-oxygenation of the arachidonic acid catalysed by COX-1 was found to be equal to 1.8 nM. Furthermore, 11 inhibits oCOX-1 with IC50 = 6.85 nM and mCOX-2 with IC50 = 269.5 nM; the corresponding selectivity index SI is equal to 39.3 against oCOX-1. 11 inhibits oCOX-1 at 0 min of incubation with 91% inhibition, whereas in the same time it does not inhibit mCOX-2. Fingerprints for Ligands and Proteins (FLAP) software calculations were performed to justify 11 higher COX-1 inhibitory potency than mofezolac (COX-1 IC50 = 5.1 nM), which in turn is a moiety of 11. Specifically, the two compounds bind differently in the COX-1 active site.

A set of novel diarylisoxazoles has been projected using mofezolac (1) as a lead compound to investigate structure-inhibitory activity relationships of new compounds and the cyclooxygenases (COXs) catalytic activity. Mofezolac was chosen because is the most potent and selective reversible COX-1 inhibitor [COX-1 IC50 = 0.0079 μM and COX-2 IC50 > 50 μM, with a selectivity index (SI) in favor of COX-1 higher than 6300]. Seventeen new compounds were synthesized in fair to good yields and evaluated for their COXs inhibitory activity and selectivity. SIs ranged between 1 and higher than 1190.3,4-Bis(4-methoxyphenyl)-5-vinylisoxazole (22) has the highest SI with COX-1 IC50 = 0.042 μM and COX-2 IC50 > 50 μM. 1 and 22 were superior to aspirin in inhibiting platelet aggregation (IC50 = 0.45, 0.63 and 1.11 μM, respectively) in human platelet rich plasma (hPRP) assay. They did not induce blood coagulation and hemolysis, and are neither genotoxic nor mutagen. 1 and 22 slightly increase bortezomib cytotoxic effect on multiple myeloma (MM) cell lines (NCI-H929 and RPMI-8226) and affects MM cell cycle and apoptosis when co-administered with the proteasome inhibitor bortezomib, a drug clinically used to treat plasma cell neoplasms including MM. In addition, structure-based binding mode of 1 and 22, through Fingerprints for Ligands and Proteins (FLAG) calculation, allowed to explain the one order of magnitude difference between COX-1 IC50 values of the two compounds. Specifically, the higher inhibitory potency seems due to the formation of a H-bond between COX-1 S530 and the carboxyl, present in 1 and absent in 22.

The interactions of a series of sterically hindered phenanthroline derivatives with first-row transition metal ions were thoroughly investigated through a combined spectroscopic study. UV–Vis titrations reveal that all the investigated systems form stable complexes with a stoichiometric metal to ligand (M:L) ratio of 1:1; furthermore, the 1:2 species can be easily obtained in solution by choosing the appropriate ratio between copper ions and the three ligands. The great sensitivity of the fluorescence emission quenching of these compounds to the presence of cations can be exploited for analytical purposes to determine the unknown concentration of cations. Femtosecond transient absorption measurements reveal peculiar excite state dynamics depending on the charge density of the metal ion considered: a higher charge density is responsible for extremely fast decays, in agreement with fluorescence quenching, while lower charge density leads to the population of a triplet excited state. Particular attention has been devoted to the copper complexes and the picture described so far was further confirmed by NMR and CW EPR measurements, although different experimental settings have to be employed. In addition, the EPR study provided: i) a deep insight into the stereochemistry of the copper(II) complexes ii) first evidence on the ligand reducing ability towards copper and iii) clear indication on the possible formation of the 1:3 complex species.

We report herein general synthetic routes to novel TEG-functionalized DPP-based co-polymers (TEG = triethylene glycol; DPP = diketopyrrolopyrrole) that display alternating TEG-substituted DPP moieties with various functionalized donor units; donor units contain moieties such as polythiophene segments decorated with thermocleavable tertiary esters or additional TEG chains and alkoxy-substituted benzodithiophenes. The synthetic approaches are based on Stille coupling chemistry or, for the first time for TEG-substituted DPP-based polymers, on direct heteroarylation polymerizations. Spectroscopic and electrochemical characterization as well as preliminary tests in photovoltaic cells are also reported.

The in silico VolSurfþ descriptors, accounting for both cationic and anionic structural features of ionic liquids (ILs) were used to develop a Partial Least Squares (PLS) model able to establish a Quantitative Structure Property Relationship (QSPR) correlation with their solvatochromic dye Nile Red polarity. The PLS model allowed prediction of ENR values for 116 ILs providing an in silico ILs polarity database.

The binding features of a sulfonato-calix[4]arene with pyridinium-based gemini guests have been investigated in water at physiological condition by NMR spectroscopy. Results provided converging evidence showing that guests having different size, shape and flexibility formed water-soluble homodimeric supramolecular capsules. The remarkably large encapsulation efficiency of the anionic calixarene host towards these bis(pyridinium) gemini guests results from the favourable combination of electrostatic and hydrophobic interactions. The introduction of short and rigid spacers between the two positively charged heads of the guest improves the efficiency of the capsule formation. The insertion of a substituent into the pyridinium ring of the guest dramatically affects both the association constants and the binding modes.

The synthesis of three push-pull cationic dyes is reported here together with a photophysical study carried out by stationary and ultrafast spectroscopies. The hyperpolarizability (β) values of the three molecules have been estimated through a simple solvatochromic method based on conventional, low-cost equipment, which had been tested previously with success in our laboratory. The investigated pyridinium salts showing strong negative solvatochromism bear the same piperidine ring as a strong electron-donor group and the same thiophenes as electron-rich π-linkers, but differ in terms of the N-substituent on the electron-acceptor pyridinium unit, namely N-methyl in compound A, N-pyrimidin-2yl in B and N-2,4-dinitrophenyl in C. The derived β values were found to increase (in the order A

Four novel push-pull systems combining a central phenanthroline acceptor moiety and two substituted benzene rings, as a part of the conjugated π-system between the donor and the acceptor moieties, have been synthetized through a straightforward and efficient one-step procedure. The chromophores display high fluorescence and a peculiar fluorosolvatochromic behaviour. Ultrafast investigation by means of state-of-the-art femtosecond-resolved transient absorption and fluorescence up-conversion spectroscopies allowed the role of intramolecular charge transfer (ICT) states to be evidenced, also revealing the crucial role played by both, the polarity and proticity of the medium on the excited state dynamics of the chromophores. The ICT processes, responsible for the solvatochromism, also lead to interesting non-linear optical (NLO) properties: namely great two photon absorption cross-sections (hundreds of GM), investigated by the Two Photon Excited Fluorescence (TPEF) technique, and large second order hyperpolarizability coefficients, estimated through a convenient solvatochromic method.

We report here a successful attempt to test a solvatochromic method to estimate the hyperpolarizability (β) of cationic push−pull chromophores. This represents a simple method, alternative to the sophisticated spectroscopic techniques often employed, which can be easily and quickly applied through equipment commonly available in a typical chemistry laboratory. The case study taken into consideration consists of nine donor−π− acceptor derivatives exhibiting the rarely observed negative solvatochromism. In these dyes the electron acceptors are positively charged methylpyridinium or quinolinium rings and the electron donors are electron rich thiophene rings eventually coupled with the strongly electron donating dibuthylamino group or piperidine. The obtained β values are enhanced in this molecular series upon increasing molecular dimensionality and conjugation as well as by increasing the donor/acceptor strength. The highest hyperpolarizability is estimated for the chromophore bearing methyl quinolinum and piperidine where the most efficient photoinduced intramolecular charge transfer is also revealed by means of state of the art femtosecond transient absorption measurements. We report here a successful attempt to test a solvatochromic method to estimate the hyperpolarizability (β) of cationic push-pull chromophores. This represents a simple method, alternative to the sophisticated spectroscopic techniques often employed, which can be easily and quickly applied through equipment commonly available in a typical chemistry laboratory. The case study taken into consideration consists of nine donor-π-acceptor derivatives exhibiting the rarely observed negative solvatochromism. In these dyes the electron acceptors are positively charged methylpyridinium or quinolinium rings and the electron donors are electron rich thiophene rings eventually coupled with the strongly electron donating dibuthylamino group or piperidine. The obtained β values are enhanced in this molecular series upon increasing molecular dimensionality and conjugation as well as by increasing the donor/acceptor strength. The highest hyperpolarizability is estimated for the chromophore bearing methyl quinolinum and piperidine where the most efficient photoinduced intramolecular charge transfer is also revealed by means of state of the art femtosecond transient absorption measurements.

The excited state dynamics of two quadrupolar polyaromatic N-methylpyridinium cations have been fully investigated in order to acquire detailed information on their photo-induced behavior. The two molecules are symmetric push–pull compounds having a D–π–A+–π–D motif, with the same electron-acceptor central unit (A = N-methylpyridinium) and two distinctive electron-donor polyaromatic side groups (D), namely naphthyl and pyrenyl substituents. Both molecules undergo charge transfer during the absorption, as revealed by a significant solvatochromism exhibited with solvent polarity, but the fate of their excited state was found to be markedly different. The careful analysis of the data gathered from femtosecond-resolved fluorescence up-conversion and transient absorption experiments, supported by DFT quantum mechanical calculations and temperature-dependent stationary measurements, shows the leading role of intramolecular charge transfer, assisted by symmetry breaking, in the pyrenyl derivative and that of rotamer interconversion in the naphthtyl one. Both excited state processes are controlled by the viscosity rather than polarity of the solvent, and they occur during inertial solvation in low-viscous media and lengthening up to tens of picoseconds in highly viscous solvents.

Photophysical properties of some azinium iodides in aqueous solution of nanostructured systems as DNA and nonionic micelles were investigated using steady-state and ultrafast time-resolved spectroscopy. Spectrophotometric and fluorimetric titrations of the investigated compounds with salmon testes DNA supplied evidence of a good interaction between the salts and DNA with binding constants of 10(4)-10(6) M(-1), making them interesting for pharmaceutical applications. The interaction with DNA also changes the photobehavior of the compounds, increasing the radiative deactivation pathway to the detriment of internal conversion and slowing down the excited state dynamics. The interaction of the azinium salts with the nonionic surfactant Triton X-100 from premicellar to postmicellar concentration was studied by spectrophotometric and fluorimetric titrations evidencing the ability of the micelles to associate the studied salts in their hydrophobic portion and to release them in the presence of DNA, acting as promising drug carriers. Also transient absorption spectroscopy with femtosecond resolution demonstrated the insertion of the investigated compounds into micellar aggregates. Preliminary measurements by confocal fluorescence microscopy on MCF-7 cells in the presence of the studied azinium salts showed that they are able to cross the cellular membrane and that their cytotoxicity can be expressed through interaction with DNA (RNA). In fact, they showed a significant fluorescence signal in all cell compartments, particularly (for 2 and 3) into punctuate structures within the nuclei compatible with a localization into the nucleoli.

A joint experimental and theoretical approach, involving state-of-the-art femtosecond fluorescence up-conversion measurements and quantum mechanical computations including vibronic effects, was employed to get a deep insight into the excited state dynamics of two cationic dipolar chromophores (Donor-π-Acceptor(+)) where the electron deficient portion is a N-methyl pyridinium and the electron donor a trimethoxyphenyl or a pyrene, respectively. The ultrafast spectroscopic investigation, and the time resolved area normalised emission spectra in particular, revealed a peculiar multiple emissive behaviour and allowed the distinct emitting states to be remarkably distinguished from solvation dynamics, occurring in water in a similar timescale. The two and three emissions experimentally detected for the trimethoxyphenyl and pyrene derivatives, respectively, were associated with specific local emissive minima in the potential energy surface of S1 on the ground of quantum-mechanical calculations. A low polar and planar Locally Excited (LE) state together with a highly polar and Twisted Intramolecular Charge Transfer (TICT) state is identified to be responsible for the dual emission of the trimethoxyphenyl compound. Interestingly, the more complex photobehaviour of the pyrenyl derivative was explained considering the contribution to the fluorescence coming not only from the LE and TICT states but also from a nearly Planar Intramolecular Charge Transfer (PICT) state, with both the TICT and the PICT generated from LE by progressive torsion around the quasi-single bond between the methylpyridinium and the ethene bridge. These findings point to an interconversion between rotamers for the pyrene compound taking place in its excited state against the Non-equilibrated Excited Rotamers (NEER) principle.

Neuroinflammation is the earliest stage of several neurological and neurodegenerative diseases. In the case of neurodegenerative disorders, it takes place about 15–20 years before the appearance of specific neurodegenerative clinical symptoms. Constitutive microglial COX-1 is one of the pro-inflammatory players of the neuroinflammation. Novel compounds 3, 14 and 15 (Galmof0, Galmof5 and Galmof11, respectively) were projected, and their synthetic methodologies developed, by linking by an ester bond, directly or through a C5 or C11 unit linker the highly selective COX-1 inhibitor mofezolac (COXs selectivity index > 6000) to galactose in order to obtain substances capable to cross blood-brain barrier (BBB) and control the CNS inflammatory response. 3, 14 and 15 (Galmofs) were prepared in good to fair yields. Galmof0 (3) was found to be a selective COX-1 inhibitor (COX-1 IC50 = 0.27 μM and COX-2 IC50 = 3.1 μM, selectivity index = 11.5), chemically and metabolically stable, and capable to cross Caco-2 cell monolayer, resembling BBB, probing that its transport is GLUT-1-mediated. Furthermore, Galmof0 (3) powerfully inhibits PGE2 release higher than mofezolac (1) in LPS-stimulated mouse BV2 microglial cell line, a worldwide recognized neuroinflammation model. In addition, Fingerprints for Ligands and Proteins (FLAP) was used to explain the different binding interactions of Galmofs with the COX-1 active site.

Recent drug discovery efforts are highly focused towards identification, design, and synthesis of small molecules as anticancer agents. With this aim, we recently designed and synthesized novel compounds with high efficacy and specificity for the treatment of breast tumors. Based on the obtained results, we constructed a Volsurf+ (VS+) model using a dataset of 59 compounds able to predict the in vitro antitumor activity against MCF-7 cancer cell line for new derivatives. In the present paper, in order to further verify the robustness of this model, we report the results of the projection of more than 150 known molecules and 9 newly synthesized compounds. We predict their activity versus MCF-7 cell line and experimentally verify the in silico results for some promising chosen molecules in two human breast cell lines, MCF-7 and MDA-MB-231.

State-of-the-art femtosecond spectroscopies and quantum-chemical methods were used to investigate the excited-state dynamics of D−π–A+ (C1) and D−π–A+–π–D (C2) methylpyridinium (acceptor unit, A) derivatives bearing dibutylamino groups as strong electron donors (D) and bithiophenes as highly effective π-rich spacers. The absorption spectra of C1 and C2 are broad and shifted to the red side of the visible spectral range. A significant negative solvatochromism was observed for the absorption bands of the investigated salts with increasing solvent polarity that was rationalized in terms of the change in electron density upon excitation. The absorption spectra of C2 are red-shifted with respect to those of C1, whereas the emission bands of the two compounds overlap, suggesting a localization of the excitation on just one branch of the quadrupolar compound, which becomes the fluorescent portion. This is in agreement with our quantum-mechanical calculations, which predict that the symmetry of C2 is broken in th...

A new series of supramolecular assemblies is obtained through the interaction of 3-pyridylmethyl-calixarenes and copper or zinc ions. The complexes formed are characterized both in solution and in the solid state. The results offer appealing insights into how the steric crowding of the lower rim and different coordination modes of the metal centers have a great impact on the overall architecture of the complexes with the formation of monomeric, dimeric, or oligomeric/polymeric species.

The synthesis of (E)-2-cyano-3-(5′-piperidin-1-yl-2,2′-bithien-5-yl)acrylic acid, a novel amyloid aggregation fluorescent probe, is reported. This new probe is able to monitor soluble oligomeric aggregates after 24 h, at which time Thioflavin T emission, commonly used to monitor amyloid fibril formation, remains unchanged. Atomic force microscopy, native polyacrylamide gel electrophoresis, and dynamic light scattering confirm that the earlier stages of aggregation are prefibrillar oligomeric species not possessing the amyloid structure. This new molecular scaffold expands the toolbox of fluorescent probes for the identification of prefibrillar oligomers, which is needed in studies aimed at the early detection of the soluble toxic aggregates that characterize the so-called protein misfolding diseases.

We report a joint experimental and theoretical investigation of a quadrupolar D-π-A(+) -π-D system, the electron donors being diphenylamino groups and the electron acceptor being a methylpyridinium, in comparison with the dipolar D-π-A(+) system. The emission spectra of the two compounds overlap in all the investigated solvents. This finding could be rationalized by TD-DFT calculations: the LUMO-HOMO molecular orbitals involved in the emission transition are localized on the same branch of the quadrupolar structure that becomes the fluorescent portion, corresponding to that of the single-arm compound. Excited-state symmetry breaking has been rarely observed for quadrupolar systems showing negative solvatochromism and is here surprisingly revealed, even in low polarity solvents. Femtosecond transient absorption measurements revealed that an efficient photoinduced intramolecular charge transfer takes place in the quadrupolar chromophore, more efficient than in its dipolar analogue. This result is promising in view of the application of these compounds as novel two-photon absorbing materials.

Five in silico principal properties (PPs) for 218 heterocyclic cations and four PPs for 38 organic and inorganic anionic counterparts of ionic liquids (ILs) were derived by the VolSurf+ approach. VolSurf+ physicochemical descriptors take into account several cationic structural features of ILs such as heterocyclic aromatic and non-aromatic cationic cores, alkyl chain length, presence of oxygen atoms in the substituents as well as the properties of a wide variety of inorganic and organic anions. Combination of these cation and anion PPs can provide descriptors for over 8000 ILs, thus allowing the development of QSPR models for IL cytotoxicity (IPC-81 rat cell line) and enzyme toxicity (acetylcholinesterase inhibition). The adoption of a Partial Least Squares approach, relating PPs and toxicities, provided affordable predictions for ILs in both learning and external validation sets, implying the possibility to extend the predictive model to a set of 520 ILs. This allows us to establish priorities in selecting ILs for experimental hazard assessment as required by the REACH regulation.

DFT calculations were used to investigate the structure and electronic properties of some analogs of 2,6-bis((E)-2-(furan-2-yl)vinyl)-1-methylpyridinium iodide which was considered as a benchmark. We focus our attention over the ability of these molecules to intercalate between the two strands of DNA indicating a potential antitumor activity. DFT optimized structures, compared with experimental biological data, allowed us to suggest that the activity decreases when the molecules deviate from geometric planarity. In this sense it is to note the role played by substituent such as the phenyl group which, giving rise to a rigid steric hindrance, obstructs the DNA intercalation. Further features make favorable the binding with DNA, in particular we underline the presence of hydrogen bond acceptor atoms and a properly disposition of the planar portion of the molecule with respect to the positive charged portion. Finally calculated binding energies between the molecules and a short fragment of DNA well describe experimental results. From these findings one can argue that the biological activity of such compounds can be related to the DNA intercalation.

OPLS discriminant analysis (OPLS-DA) was successfully applied for the selection of a limited number of gene transcripts necessary to discriminate PTPN11 and RAS mutated cells in acute lymphoblastic leukaemia (ALL) patients. The original set of 273 variables with VIP (1) values higher than 2.0 in the OPLS-DA model could be further reduced to 200 by elimination of less informative variables in the PCA class models adopted for SIMCA classification. The above 200 transcripts not only achieve a satisfactory discrimination accuracy between PTPN11 and RAS mutated cells but also indicate clearly that wild type samples belong to none of the mutated class models. In this list it was possible to identify candidate genes that could be involved in the molecular mechanisms discriminating PTPN11 and RAS mutations in ALL. Among them CBFA2T2, a member of the "ETO" family, is known because of its homology and association with the product of RUNX1-CBFA2T1 gene fusion generated by t(8;21) translocation, one frequent cause of acute myeloid leukemia.

The kinetics of oxidation of p-X-benzyl phenyl- and p-Y-phenyl benzyl sulfides by V(V) oxo–monoperoxo complex [PicVO(O 2 )] (Pic = picolinic acid anion) in acetonitrile at 20 °C is reported. The oxidation reaction leads to the formation of the corresponding sulfoxides and to oxygen produced from the oxidant decomposition started by the substrate. The change of the obtained sulfoxide-emitted oxygen ratio in p-Y-phenyl benzyl sulfides seems to be due to the substituent type used in the substrate, whereas when the substituent is isolated from the reaction centre, as in p-X-benzyl phenyl sulfides, the sulfoxide and oxygen emitted are not influenced by the substituent. Moreover the products obtained from the oxidation of some p-X-toluenthiols (the corresponding aldehydes) suggest the hypothesis of a possible pathway for the oxygen transfer step for these reactions. The process seems to require coordination of the organic sulfide to the metal, followed by oxidation within the coordination sphere.

The synthesis and spectroscopic characterization of trans 1-(indol-2-yl)-2-(1-methylpyridinium and 1-methylquinolinium-2-yl) ethylenes is reported. In vitro antitumour activity tests show that quinolinium derivatives are more active towards MCF7 (breast), LNCap (prostate) and U87 (human gliobastoma) carcinoma cells than pyridinium ones.

The effects of pH on the spectral properties of stilbazolium salts bearing dimethylamino substituents, namely, trans isomers of the iodides of the dipolar E-[2-(4-dimethylamino)styryl]-1-methylpyridinium, its branched quadrupolar analogue E,E-[2,6-di-(p-dimethylamino)styryl]-1-methylpyridinium, and three analogues, chosen to investigate the effects of the stronger quinolinium acceptor, the longer butadiene π bridge, or both, were investigated through a joint experimental and computational approach. A noticeable acidochromism of the absorption spectra (interesting for applications) was observed, with the basic and protonated species giving intensely colored and transparent solutions, respectively. The acid–base equilibrium constants for the protonation of the dimethylamino group in the ground state (pKa) were experimentally derived. Theoretical calculations according to the thermodynamic Born-Haber cycle provided pKa values in good agreement with the experimental values. The very low fluorescence yield did not allow a direct investigation of the changes in the acid-base properties in the excited state (pKa*) by fluorimetric titrations. Their values were derived by quantum-mechanical calculations and estimated experimentally on the basis of the Forster cycle.

A novel set of 1,4-diaryl-1,2,3-triazoles were projected as a tool to study the effect of both the heteroaromatic triazole as a core ring and a variety of chemical groups with different electronic features, size and shape on the catalytic activity of the two COX isoenzymes. The new triazoles were synthesized in fair to good yields and then evaluated for their inhibitory activity towards COXs arachidonic acid conversion catalysis. Their COXs selectivity was also measured. A predictive pharmacometric Volsurf plus model, experimentally confirmed by the percentage (%) of COXs inhibition at the concentration of 50 μM and IC50 values of the tested compounds, was built by using a number of isoxazoles of known COXs inhibitory activity as a training set. It was found that two compounds {4-(5-methyl-4-phenyl-1H-1,2,3-triazol-1-yl)benzenamine (18) and 4-[1-(4-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-yl]benzenamine (19)} bearing an amino group (NH2) are potent and selective COX-1 inhibitors (IC50 = 15 and 3 μM, respectively) and that the presence of a methylsulfamoyl group (SO2CH3) is not a rule to have a Coxib. In fact, 4-(4-methoxyphenyl)-5-methyl-1-[4-(methylsulfonyl)phenyl]-1H-1,2,3-triazole (23) has COX-1 IC50 = 23 μM and was found inactive towards COX-2.

Three novel donor-π-acceptor molecules with a bis-thiophene core have been synthesized through a simple and versatile metal-free synthetic procedure. Study of their optical and electrochemical properties, and a preliminary evaluation of their use as dyes in dye sensitized solar cells (DSSC) are presented. The proposed synthetic protocol results in a drastic reduction of the size and complexity of the sensitizer molecule, possibly enabling cost decrease by overall yield improvement and easy scalability. Particular attention has been paid to limit the environmental impact by reducing the number of synthetic steps and especially avoiding the use of organometallic reactions.

A theoretical study of the dimerization of amphiphilic Schiff-base bis(salicylaldiminato)Zinc(II) complex (1) in dichloromethane with and without pyridine, is reported in this paper. A comparative investigation between experimental and calculated 1 H NMR and UV–vis spectra was performed to evaluate the percentage contribute of each conformer in non-coordinating solvent. DFT calculations and a detailed analysis of the rotational barrier were carried out to study various dimer aggregate. Gibbs free energy related to the dimerization process, in presence of pyridine, was also estimated. Results highlight that in solution of non-coordinating solvent are mainly present three different conformers ( D1 , D2 and D3 ) which can convert each other at room temperature. Moreover, it was confirmed that dimerization is a favored process in the non-coordinating solvent. Without a doubt, best fit procedure demonstrates that the greater contribute to the dimers distribution in solution, is due to conformer D3 . UV–vis bands were also assigned to the corresponding electronic transitions. Finally the dimerization process is, thermodynamically, not favored in presence of pyridine. In this case the stable complex monomer–pyridine is formed.

A multivariate insight into lanthanide triflates descriptors allowed derivation of three principal properties (PPs). The first one resembling the lanthanide sequence in the periodic table, the second one reflecting the discontinuity in lanthanides properties, the so called 'gadolinium break', and the third one related to the change of coordination number of Ln ions in aqueous solution from nine to eight around Sm–Gd. Experimental support to the predicting ability of the above PPs as descriptors in the prediction of the yields for the synthesis of α-tocopherol from a selected set of four triflate catalysts (La, Eu, Er, Lu) was provided, opening new horizons for a rational selection in multivariate experimental design of Ln triflates catalysed organic reactions. Copyright © 2007 John Wiley & Sons, Ltd.

Partial least squares discriminant analysis (PLS-DA) provides a sound statistical basis for the selection of a limited number of gene transcripts most effective in discriminating different lung tumoral histotypes. The potentialities of the PLS-DA approach are pointed out by its ability to identify genes which, according to current knowledge, are considered molecular markers for colon cancer diagnostics and classification. Indeed application of PLS-DA to in vivo data allowed identification of a set of genes able to discriminate primary lung tumours from colon metastases.

Structural patterns for antitumor drugs, evidenced by means of a molecular interaction field (MIF) approach using grid independent descriptors (GRIND), resembled closely those of a previous independent pharmacological classification based on their antitumor mechanism of action. For topoisomerase II inhibitors, antimitotic agents and DNA antimetabolites, systematic structural patterns were evidenced by MIF and the structural features of "outliers" in these classes corresponded to peculiar pharmacological mechanisms of action supported by literature evidences. Alkylating agents and DNA/RNA antimetabolites, interacting with a large variety of targets by different molecular mechanisms, did not exhibit clustering in the structure-based MIF approach. Moreover MIFS were able to point out similarities between drugs which, in spite of apparent dramatic differences in chemical structure, exhibit the same pharmacological behaviour.

Partial least squares discriminant analysis (PLS-DA) provides a sound statistical basis for the selection, from an original 9605-data set, of a limited number of gene transcripts most effective in discriminating different tumour histotypes. The potentialities of the PLS-DA approach are pointed out by its ability to identify genes which, according to current knowledge, are associated with cancer development. Moreover, PLS-DA was able to identify MUC 13 and S100P proteins as candidates for the development of new colon cancer diagnostics. Various genes with unknown function and ESTs (expressed sequence tags), found to be important in discriminating genes for colon, leukaemia, renal and central nervous system tumour cells, are indicated as deserving high priority in future molecular studies. Copyright © 2004 John Wiley & Sons, Ltd.

The in vitro antitumor activities of 2,6-di-[2-(heteroaryl)vinyl]pyridines versus the standard National Cancer Institute 60 cell lines panel and of 2,6-di-[2-(heteroaryl)vinyl] pyridinium cations versus MCF7 (human mammary carcinoma) and LNCap (prostate carcinoma) cell lines are reported. Antiproliferative effects in both series are particularly evident for MCF7 mammary adenocarcinoma cells. Multivariate analysis of DNA microarray data for responsive tumor cell lines suggest a mechanistic pathway involving polyamine biosynthesis and prolactin signal transduction.

The effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles have been studied to design new potent antibacterials against Gram-positive multidrug-resistant pathogens. The adopted strategy involved a molecular modelling approach, the synthesis and biological evaluation of new designed compounds, enantiomers separation and absolute configuration assignment. Experimental determination of the antibacterial activity of the designed (S)-1-((3-(4-(3-methyl-1,2,4-oxadiazol-5- yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea and (S)-1-((3-(3-fluoro-4-(3-methyl-1,2,4- oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea against multidrug resistant linezolid bacterial strains was higher than that of linezolid.